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Karthus Build Guide by Retribution

Karthus: Another Requiem. A Comprehensive Guide.

Karthus: Another Requiem. A Comprehensive Guide.

Updated on November 28, 2012
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5,199 Views 7 Comments League of Legends Build Guide Author Retribution Karthus Build Guide By Retribution Updated on November 28, 2012
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Choose Champion Build:

  • LoL Champion: Karthus
  • LoL Champion: Karthus
  • LoL Champion: Karthus

Spells:

LoL Summoner Spell: Exhaust

Exhaust

LoL Summoner Spell: Flash

Flash

Introduction.

*This guide is still in progress. With the S3 patch coming up, I'll be busy updating everything. Maybe I shouldn't have started the guide this early xP.*

Hello everyone! Retribution here. This is my fourth guide here on Mobafire, for Karthus, the Deathsinger.

Karthus is an amazing champion, and one who can single-handedly carry games if played correctly. He is a champion that is incredibly easy to farm with using Lay Waste and Defile, has a very strong slow in Wall of Pain, as well as a global presence with Requiem. He has a significant influence on teamfights, but does require some skill to play. Death Defied is, IMO, one of the most useful passives in the entire game. It allows you to continue casting spells for 7 seconds, which is a LONG time in a fight.

You, as a reader, do not have to agree on my methods. I understand that everyone has a different gaming style, and the reason I'm here is to provide you with my own ideas. Feel free to give me suggestions and the sort if you disagree with me. Perhaps I can try the suggestions out, and they may work better than my ideas. Give me an up-vote if you like my guide, and feel free to down-vote if you disagree. However, please, if you're going to down vote, specify why. Apparently you can get banned if you down-vote, and all you say is "Nope", "Ew", and stuff like that ._.

If you liked my guide, check out my other ones!
Lux: The Final Spark. A Comprehensive Guide.
Ezreal: A True Display of Skill. A Comprehensive Guide.
Sona: With Perfect Tempo. A Comprehensive Guide.
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Pros and Cons.

Pros
+Easy to farm with!
+AoE spells!
+ Lay Waste can hurt a lot!
+Global ultimate!
+ Wall of Pain gives vision!
+One of the best Soft-CCs in the game!
+Passive Mana-Regen in Defile!
+ Death Defied. Need I say more? ;D
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Cons
-Hard to master.
-Terrible auto attack animations.
-Lack of escape tactics.
- Requiem can be interrupted with CC.
-Mana-hungry early.
-Needs to be in the middle of the fight.

With all that said, Karthus is actually a decent champion. The Pros are actually really useful, and you can counter just about all the Cons.

Hard to master. This is the only one that requires more work, because it means you have to practice with him a bit more.
Terrible auto attack animations. NP. Use Lay Waste and Defile to farm.
Lack of escape tactics. Simple. Don't push too hard, and keep your lane warded. Wall of Pain if they try to chase, but don't miss it.
Requiem can be interrupted with CC. Cast from behind turret, in a safe bush, or while Death Defied is active.
Mana-hungry early. Don't use too much mana to farm. You have passive regen from Defile anyway, don't worry about harassing just yet.
Needs to be in the middle of the fight. Zhonya's Hourglass, Abyssal Mask, Death Defied. That should be all you need.
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1.1: Typical rune sets.

Runes

Precision
Fleet Footwork
Phase Rush

This is my current rune setup. The Greater Mark of Magic Penetration give MP, which increases our damage done by spells, by ignoring some of the target's MR. Along with our Sorcerors shoes, this will allow our abilities to deal their full damage early game. Our Greater Seal of Replenishment gives us some Mana Regen, which is very useful towards controlling the amount of mana consumed through the use of abilities. Greater Glyph of Scaling Ability Power provide us with some much needed AP, and along with Greater Quintessence of Ability Power you'll be doing quite a bit of damage early game!
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Greater Seal of Armor gives us armor for the laning phase. Many AP mids like to harass using auto attacks early on, and they build up pretty quickly. Using this will allow you to survive. Also good if laning against Talon.
greater seal of vitality gives us a lot of late game health, which allows us to stay alive that much longer. Since you'd be in the middle of a fight, the extra health can be quite useful.
Greater Glyph of Magic Resist gives us a good amount of MR, allowing us to survive in the lane by taking less damage. However, you'd be sacrificing some late game AP by using this.
Greater Glyph of Ability Power gives us flat AP, as opposed to AP per level. This is better for early game damage, but the AP/Lvl is more useful late game. Since runes usually fall off by mid-game, it's up to you which to take. I'm not sure if it's entirely viable, but I like to use a mixture of the two.
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1.2: Usual Mastery Trees.

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1.3: Summoner Spells.

This is an absolute must on Karthus. First, you have no reliable escape tactic in lane, except for Wall of Pain. (Which means Master Yi will screw you over) Also, you will be using this to engage fights at times. It might not be as effective as Morgana with Soul Shackles, but it works just fine.
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This spell is quite useful all game. This, along with Wall of Pain, can easily get you a kill during the laning phase. This also serves as a defense mechanism against jungler ganks, since most of them rely on physical, auto attacks. Finally, using this correctly in a teamfight will effectively shut down an enemy, preferrably the enemy AD Carry.
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Despite its long cooldown, this is a good spell to have in any team composition. While you don't have the killing potential of Exhaust, this grants you good mobility and map presense. You can use this to gank side lanes, or return to your own lane quickly. Late game, it can be used to join fights quickly and unexpectedly.
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While being a standard pick on most AP Carries, I don't usually take this on Karthus. His spell set just benefits more from taking Exhaust, and if the enemy escapes with a sliver of health you can always just use Requiem. About the only time when I would use this is when the enemy has someone like Vladimir.
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1.4: Karthus's Skill Set.


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Passive: Death Defied. Upon dying, Karthus enters a spirit form allowing him to continue casting spells for 7 seconds. During this time his abilities cost no mana. This passive allows Karthus to be a strong team fighting member, as he can help out even after dying. During this time, he is only bound by cooldowns, and can cast anything within the time period with no concerns to mana. Defile will be active as long as there is at least 1 point in the skill.
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-Because of this passive, we want to be in the middle of a team fight, if possible.
- Flashing into the enemy team is a really dangerous move, avoid it if anyone else on your team can engage a fight.
-All spells can be cast during the time, but Requiem must be cast within the first half of the time frame.
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Q: Lay Waste. Creates a delayed blast at Karthus' cursor position. After 0.5 seconds, deals 40 / 60 / 80 / 100 / 120 (+30% of ability power) magic damage to each nearby enemy. This deals double damage if it hits only a single unit. This spell makes Karthus a strong champion in the solo lane, as well as a strong farmer. This spell has extremely low mana costs and cooldowns, so it's fine to spam it. In fact, that's what you usually want to do when fighting enemies. There is a slight delay, so make note of that. This also works well to farm minions in lane.
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-This spell allows Karthus to farm in lane easily, but don't use it on minions except for last hitting.
-You COULD run out of mana by using this too much.
-This provides minimal vision in the blast zone, so use it for basic bush checking.
-This skill is smartcasted by default, meaning it would cast wherever your mouse is located.
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W: Wall of Pain. Creates a 800 / 900 / 1000 / 1100 / 1200 distance wide wall through target point. Reduces enemy magic resistance by 15% and reduces movement speed by up to 40 / 50 / 60 / 70 / 80 %; debuff lasts 5 seconds. The wall lasts 5 seconds. This is Karthus's only form of cc. It is perhaps one of the strongest "soft-cc"s in the game. Even at level 1, the slow is quite significant, AND it reduces the target's MR. The wall length increases by level, and you can pretty much cover entire lanes with this once it's maxed. Wall of Pain is your only source of escape, and it's got a long cooldown as well as a high cost early game, so use it wisely. It provides you with heck of a lot of vision, too.
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-This spell gives you and your allies vision around the wall, for 5 seconds.
-Can be used to escape or chase.
-Use to engage team fights from a distance.
-There is a very small delay, so you want to lead your opponents with the wall. Not too much lead, though.
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E: Defile. Toggle Off: When Karthus kills a unit, he restores 20 / 27 / 34 / 41 / 48 mana. Toggle On: Drains 30 / 42 / 54 / 66 / 78 Mana to deal 30 / 50 / 70 / 90 / 110 (+25% of ability power) damage to nearby enemies each second. This spell grants us AoE damage around us as long as the spell is active. The spell damage late game is quite high, actually, but is sort of weak early game. It does drain quite a bit of mana, but it passively restores mana like Swain's Carrion Renewal. This spell is automatically activated upon Death Defied's activation.
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-This spell can be used to farm creeps, but only for that last hit. It's hard to time because of the low damage early on. It also drains quite a lot of mana.
-Like other AoE DoT's, such as Tormented Shadow, the first tick of damage is immediately dealed upon activation.
-When you have enough CDR, spamming the E key instead of keeping the ability active WILL deal higher DPS. If you have the patience :P
-This only activates on Death Defied if you have at least 1 point in the skill.
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R: Requiem. After channeling for 3 seconds, Karthus deals 250 / 400 / 550 (+60% of ability power) magic damage to all enemy champions (regardless of distance). This is one of the most useful skills to use, as well as the most annoying to play against in the game. Basically, you deal damage to everyone by pressing R. While the early damage isn't so high, the late game damage is quite significant. You can use this to pick off low-health enemies from your lane or another lane, if your allies can't secure the kill. This can also be used as a supportive move: You're helping your allies in another lane to kill your opponents by taking down a big chunk of their health. YOU DON'T ALWAYS HAVE TO KILL WITH THIS SPELL. This can also be used before starting a team fight, to give your team an advantage in terms of health, as well as damage, since the carries will more than likely have Executioner active.
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-This CAN be cancelled by hard CC during the 3 second casting time, such as stuns and silences.
-Casting this while Death Defied is active can NOT be interrupted in any way. Meaning, feel free to do it once you're dead in a fight.
-Don't "Rage-ult", unless you can kill an opponent. It has a long cooldown.
-Never, ever, EVER kill steal with this.
-Enemy spells such as Sanguine Pool and Playful / Trickster can dodge this.
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1.5: Typical Skill Sequence.

Ability Sequence
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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I almost always start off Lay Waste at level 1, because it is an extremely versatile skill, even at this low rank. It works great for harassing opponents, farming creeps, and checking bushes for potential enemy invasions. Alternatively, you can start off Wall of Pain for invading the enemy, as the cc would prove quite useful. However, that would set you back in the laning phase, so I don't recommend it.
Assuming I started off with Lay Waste, I usually go for Defile at level 2. This further improves our farming potential, as well as increasing our mana pool. Since we restore mana on killing a target, we should not be running out of mana, since Lay Waste costs quite little. Levelling up Wall of Pain is good for more aggressive play, and is typically geared towards receiving a level 2 gank. Combined with Exhaust, this will easily secure a kill for you in lane. However, you will have a reduced mana pool, limiting your ability to farm.
Afterwards, I always max Lay Waste first, since it is our main source of damage output. The spell's single target damage is deceptively high, and it is efficient in clearing minion waves as well. Level up Wall of Pain second, for the improved cc and range. Defile isn't a good investment until late-game, because the mana draining will be too much for us to handle early game, and it requires a decent amount of AP to be of any effect.
Of course, Requiem at 6, 11, and 16.
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2.1: Starting items.

This is the standard starting item for just about any AP carry, and it works well for Karthus as well. The improved move speed gives us safety in lane, as it will provide us with some form of escape from jungler ganks. Also, it helps to avoid skill shots from the enemy, so we can take less damage. Early game Karthus is pretty darn vulnerable, so try not to get hit, if possible. Having three potions will also allow us to stay in lane for an extended period of time.
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This is the choice to start the game if you are new to Karthus, and is building Archangel's Staff. By building this, you can rush your Tear of the Goddess, like Ryze. This will grant you good mana early game, for harassing and farming, but you will be lacking mobility to avoid skill shots and ganks. The amount of survivability you have on you will also be less than that of Boots.
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2.2: Various boots.

These boots are my standard choice for 90+% of all games. These are among the best boots you can get as an AP Mage, and basically allow you to ignore a part of the enemy's MR. Along with our masteries and runes, we will be dealing close to true damage early game. Scaling into late-game, this allows you to take out part of the target's MR, and has "infinite range", meaning it applies to Requiem as well.
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These boots are a good choice if you are up against a team with heck of a lot of cc. The reduction will help out greatly in a fight, and enables you to deal higher DPS since you don't have to worry as much about getting CCed. This also grants a bit of MR for laning and the rest of the game. However, you will be lacking some damage, due to not having the MPen from Sorcerer's Shoes.
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NOT:
For AP Mages, these are usually the "runner-up" choice for boots. The CDR works well to allow us to use abilities more often, since that's essentially all our damage output. However, Karthus doesn't need CDR AT ALL. Lay Waste already has virtually no cooldown, Defile can just be kept on for the duration of the fight, and Wall of Pain's base cooldown makes it only usable once in a typical fight anyway. While Requiem will benefit from this, it's not worth the MPen you sacrifice by not buying Sorcerer's Shoes.
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While the armor can be nice, it's not worth it, trust me.
They don't give you anything except speed.
You'd be in the middle of the fight most of the time.
Just NO.
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2.3: Core items.

Despite being "useless" on some champions, this is actually an amazing item on Karthus. The bonuses we gain from this item all benefit us well. From this, we get good AP, and a massive amount of health and mana. Since we will be in the middle of the fight, those stats will allow us to survive longer. Essentially, this item works for all short-ranged mages that rely on sustained damage rather than burst.
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This item is the most important AP item you can get, since it gives you, well, pure AP. Core on just about every AP carry, Karthus is no exception. By the time you buy this item, your damage will skyrocket. While this is kind of expensive at 3.6k, it is the best AP item you can get. Rush this as soon as possible, only after Rod of Ages because we want the passive to charge up ASAP.
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2.4: Archangel's Staff.

I've had mixed opinions about this item being purchased in general. Obviously it's amazing on a champion like Ryze, but does Karthus benefit from this, and do the benefits out-weigh the defects?

While the item is quite expensive, it's just amazing on Karthus, IMO. Along with Rod of Ages, you will benefit a lot from the passive of the item. However, buying this will force you to purchase Tear of the Goddess early game, which will delay the purchase of your other items. Some players find that Rod of Ages alone grants them enough mana.

Synergizes well with Karthus's spells. Considering how mana dependent we are throughout the game, this could be a good idea. Charging Tear of the Goddess won't be too much of a problem either, considering how much we will be spamming Lay Waste. Also, buying Tear of the Goddess early on will grant you a near-infinite mana pool, at least from my experiences. However, you will be more vulnerable due to not buying catalyst the protector until later, as well as a reduced damage output early game. The latter problem, however, gets resolved by late game.

Works well with our other items. Archangel's Staff's bonus AP is based on the total amount of mana you have. This means, the more mana you incorporate into your build, the more damage you will do. Consider this: Rod of Ages gives us a whopping 725 mana, which gives us roughly 22 ap from the bonuses. That may not seem like much, but we also have our base mana, our masteries, as well as the 1000-mana passive from the item itself. Add all that together, I usually earn around 90-120 extra AP from the item's passive. The item itself also grants 45 AP, meaning that this item will be a great contributer to our late-game damage.
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Delays your build. If you decide to purchase this item, the rest of your build would have to be delayed due to the nature of Tear of the Goddess's passive. While it's only around 1k gold, this means that you won't be able to purchase Rod of Ages and Rabadon's Deathcap as fast as you normally could. Also, you will be lacking the survivability gained from an early catalyst the protector. While we gain better overall bonuses late game, our early/mid game will be somewhat tougher.

Expensive. Honestly, this item is somewhat overpriced. Considering the measly bonuses it gives us without additional mana, the pick is controversial. True, it gives exceptional damage if fully charged, but can prove to be a liability if you build incorrectly. While Karthus is a champion that can charge Tear of the Goddess fairly quickly, buying this item without other mana items such as Rod of Ages is a bad idea.
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Personally, I feel that Archangel's Staff is best suited to more advanced players, as they would know how to play safely without the added sustainability. However, newer players could also try this, as they would probably deplete their mana supply quite quickly.
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2.5: The rest of your build.

Despite the nerfs to this item, I still consider this a good pick. This is the single AP item that grants us the most MR, and also gives us a good amount of AP, as well as an aura. As Karthus, you will be in the middle of a fight, using Defile to deal AoE damage. While you have Zhonya's Hourglass, you could still die easily. Well, if we die we have this nice contraption called Death Defied, but staying alive longer is definitely good. The aura is also put to full effect when we are in the middle of the team fight. Great item in general.
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Considering we'd constantly be in the middle of a team fight, we will need the armor. Also, the active can save us in extreme circumstances as well. Defile remains active while in Stasis, at least as far as I can remember. (Short term memory FTW :P) Anyways, this item also gives us a whopping 100 AP, second only to Rabadon's Deathcap. I consider this item to be a great pick on just about any AP carry, and I usually buy either this or Abyssal Mask first after Rabadon's Deathcap, depending on the other team's composition.
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On Karthus, this is an amazing item. The item itself is not too expensive, and it gives a nice amount of AP. The aura can be effectively used, since you would be in the middle of a team-fight. The passive spell-vamp from this can also allow you to survive longer in a fight. If another player on your team purchases this item, the aura can STACK for everyone with the item.
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2.6: Other AP items: My ideas.


7 / 10
While being one of the most cost effective items in game, Karthus does not need the mana regeneration stats. However, it could be a good choice if you purchase it for other stats. It gives good AP, a chunk of MR, as well as some CDR.
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3 / 10
This item was never particularly good on Karthus to start with, IMO, since you should be building AP with sustain, and not burst. This item was nerfed, where the active was severely crippled, and it no longer provides CDR. Thus, this really is a bad choice on Karthus.
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1 / 10
Honestly, I don't even want to know why you might consider this item. This only really works on champions like Akali and Katarina, and Karthus's auto attack animation is just horrendous.
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4 / 10
Being an avid Lux and Ezreal player, I am a fan of this item. However, Karthus has no need for this. True, the stat bonuses are nice. However, we put the passive to waste, since Karthus has terrible attacking animations like previously mentioned. Other items can give us these stat bonuses.
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6 / 10
This snow-balling item works well to get strong early on, and devastate your opponents late game. However, Karthus just doesn't need this item. Being at close range to opponents, your chances of dying are pretty darn high. Need I say more?
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2 / 10
Despite giving us Tenacity bonuses, this is a pretty darn useless item. If you're finding that you're getting hit hard by cc, just buy Mercury's Treads. This is a waste of a slot.
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5 / 10
The stats this item gives isn't too bad, and can be built from a kage's lucky pick from early game. This isn't too expensive either. However, there are better choices. I almost never use this since Athene's Unholy Grail's release.
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1 / 10
This item just isn't viable on Karthus. The AP is really small for its cost, and the AS is useless with a slow attack animation. Also, the CDR is kind of big, since we should be having the blue buff, which grants us a 20% boost. Buying this as well will exceed the 40% cap, so there's no point. BTW, Karthus = / = Teemo.
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8 / 10
This is actually a really nice item to have on Karthus. The AP's not bad, and the Health boost allows us to be quite tanky when combined with Rod of Ages. We also put the slow effect to use when we activate Defile in the middle of a fight. This is one of my top replacements.
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9 / 10
This item is a great replacement to Abyssal Mask, and you should buy it when the enemy team is heavy on MR. If the enemy each have less than 100 MR, Abyssal Mask will benefit you more, but there is no range limit to Void Staff's damage bonus, meaning Requiem would hurt more. You decide.
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3.1: When to pick Karthus? (Or any other champion)

As previously mentioned, Karthus is a champion that can single-handedly carry games. He does work in almost every team composition, since the range on his spells aren't as low as say, Veigar, yet is a huge influence in team fights due to his Area-of-Effect nature.
When picking your champion, there are a few things to consider.
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1. Know your champion.
This is more limited towards ranked competitive gaming. I mean, the purpose of normal games is for you to get used to gameplay, like Co-op mode. Anyways, in a ranked game, you don't want to pick a champion that you are inexperienced with. Chances are, you won't do so well, and you'll get hated on by your teammates if you end up feeding. I suggest playing at least 20 normal games, and having a good CS score and KDA average before moving on to play ranked as that champion.
CS scores usually depend on your laning opponent and the length of the game. Ideally, you want AT LEAST 100 cs by the 15 minute mark. As Karthus, that should be quite easy to achieve.
By decent KDA, I generally mean something over 3.0, with several more kills than deaths. Some players think they are carrying the game when they have a score of 11/10. They may have the most kills, but they likely have the most deaths as well. I consider that feeding. (Excuse me for my pessimistic perspective.)
Also, you have to be confident that you know the champion well. Ideally, you want to be able to "master" a champion before moving on. You should know the champion's abilities, their uses, and how the champion themselves work. This is not limited to Karthus, but any other champion that you intend to play.
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2. Consider your team's composition.
When playing Karthus, you usually want to have a composition geared towards team fighting, as opposed to poking. For example, champions like Maokai would be a great addition to your team. Since you *SHOULD* be picking mid lane last, you should know who your teammates are picking, and what champion suits this composition the best. While Karthus is a viable addition to just about any team composition, I find that a team fighting composition aiming for late game works best.
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3. Don't counter pick yourself.
While this can play a significant factor for your early game, I don't consider this as important as the previous 2. Reason being, you likely won't know your opponent's skill level. Let's say that your opponent picks a champion that counters you. If both of you have the same skill level, your opponent would win. However, if you have a skill level superior to your opponent, you might actually end up winning the lane. Other factors affecting the outcome include jungler presence, item choices, and more.
At ratings below, say, 1.6k, that rating, which is *SUPPOSED* to reflect your ability, is often inaccurate. At the end of Season 2, you may have seen a sudden rise in elo in the community, so that many people achieved a Gold rating. While some of them might have achieved that purely because of their skill level, others might have achieved it due to pure luck with the matchmaking system. I mean, most of the time, one "pro" can not carry four "feeders", unless the opposing team is also "really bad". Over the past few months, I got myself out of the 800s, and is now in the 13/1400 range. If anything, the 800 range feels more competitive than my current level. While I was in the 800s range, I can often expect games to go on for 40-50 minutes, because the teams' skill level are mostly equal. (Maybe part of that was due to my preference of playing Lux, who doesn't have as much of an ability to carry games compared to other mid lane champions like Ahri.) However, I have not had a good game in weeks. 90% of the games I play now, one of the team surrenders due to someone feeding 0/7 at 20 minutes, or something like that.
Back on topic. Counter picking yourself is not a smart move to make, but remember that if your opponent picks a counter, that does not mean a guaranteed loss for you. Play more passively, and ask your jungler to visit more often, and you should be able to live through the laning phase. Also, do not always aim to "counter" your opponent's pick, because you don't know if their skill level is higher, if they are experienced with their champion, etc.
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In conclusion, you usually want to pick a champion that you are confident and experienced with, works well with your team composition, and not counter yourself. This applies to any pick in the game, not just Karthus, or AP Carries.
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3.2: Farming as Karthus.

Karthus has like THE worst auto attack animations in the game, no contest.
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Because of that, Karthus is not like other mid lane champions, where you can farm easily by last hitting minions with an auto attack.
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However, do recall that we have:

This is a spell that costs a minute amount of mana, has close to no cooldown, and deals AoE damage.
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We also have:

From this, we gain a certain amount of mana whenever we kill an enemy, much like Swain's Carrion Renewal. Also, this spell's active deals AoE damage around you at a decent range. The first tick of damage is applied immediately upon activation.
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With these two spells, it almost seems like the champion designers want to "force" you to farm using skills, and not the "Uber-slow auto attack".
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Your easiest method of farming would be using Lay Waste. At earlier levels, you should never be running out of mana by using this, due to the regeneration from Defile. The damage from this spell is also approximately equal to that of your auto attacks. While there is a slight delay upon casting, it isn't that hard to learn, since it would be approximately equal to the auto attack delay on other mid lane champions.
Defile is a method that is somewhat "less" reliable. The early-game damage of this spell is *VERY* low, only dealing around half your auto attack damage. However, this works well if you have multiple low health minions closeby. Lay Waste one of them, and Defile the other.
Once you get used to Karthus, auto attacking for last hits in between spells would put your farming at an efficient rate.
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3.3: When to use Requiem.

YOU DO NOT HAVE TO GET A KILL WITH YOUR ULTIMATE.
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This is a common misconception when it comes to playing Karthus. You do not have to kill a target with this! A good use would be casting this as a signal for a side lane to engage a fight, or if the enemy is diving an ally under a tower. If used correctly, it can change the outcome of a skirmish, usually in your team's favor. Assists might not be as appealing as a kill, but it's always good to help an ally in need.
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Do NOT cast your ultimate in a place where you can easily be interrupted, by either hard cc or death. The 3 second casting period will leave you exceptionally vulnerable to attack. Also, the cooldown timer starts the moment you start casting this. Meaning, if you are interrupted, the cooldown stays there without the actual spell being cast. Any kind of hard CC like stuns, knockbacks, and silences can interrupt this. Dying while casting can also interrupt this, despite you having the Death Defied passive. The best thing to do when in lane is to go behind your turret to cast the ultimate. You might tell me that you're losing on CS and experience. Two methods to counter that are: Don't push your lane past the river, OR completely pushing your wave before you return to your tower to cast Requiem.
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(Trying to do this when you are against a Lux is perhaps one of the most annoying. She has one of the longest conventional range of mid lane champions, losing only to champions like Xerath and Twisted Fate. She also has an exceptional amount of burst damage that can be cast at 1000 range, unlike the other champions I mentioned. By level 6, she can easily burst you down from anything under 3/4 health, even if you are under your turret. The cast time of her combo can be as little as 0.7 seconds with smart spellcasting enabled. I suggest completely pushing your wave, as opposed to not push too far.)
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After the laning phase, Requiem will be dealing quite a lot of damage. In a team fight, this spell alone can change the outcome of the fight, hence why Karthus can carry games easily. By max level, this spell can take away at least 1/4 of the opponent team's health, and even more from the squishier carries. As Karthus, you would be in the middle of a fight. Considering that, the best time to cast this would be after you die, when Death Defied is active, to allow your allies to finish off your opponents. There is NO way anyone can interrupt you from casting Requiem when you are on Death Defied. Alternative usages may be before engaging a fight to give your team an advantage, although smarter enemies won't let you engage on them when you have a clear advantage. Casting it after the fight can also work, to pick off that remaining straggler. Just remember, do NOT cast this in the middle of a fight unless you are already dead.
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Changes Log.

2012/11/27: Guide published!
2012/11/28: Pending various suggestions, I have removed Athene's Unholy Grail.
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