Difficulty

There are four difficulty levels in Left 4 Dead. Each level refers to the difficulty of the campaign, and each has drastic differences over the next. For example, on the Easy difficulty, it's rare to see a horde outside of the occasional Crescendo Event, whereas on Expert it's likely you'll face a horde around every corner. The specific differences between each difficulty level are listed below.

Easy
As the name suggests, this difficulty is the easiest of the four. Players receive an abundance of health packs. Common Infected die from a single pistol shot, meaning that a single player with a pistol can decimate a horde in seconds. Shotgun shells kill Infected at sniper range. This mode would be recommended for beginners and those who simply want to relax. This is also an easier way to get achievements without the trouble of the harder difficulties.

Details

 * The Tank has 3000 health points, does 24 damage per hit and 75 when pounding.
 * The Witch has 500 health points and is startled in 8 seconds.
 * Friendly fire does not inflict damage, but friendly fire incidents will still register and disqualify players from earning the Safety First achievement.
 * Molotov cocktails and gas cans, once ignited, can still cause damage to other Survivors, so watch where you throw them. In addition, detonating a propane tank, pipe bomb, or oxygen tank will also do friendly fire damage.
 * Common Infected inflict 1 point of damage per hit, 0.5 if attacking a Survivor's back.
 * The Smoker does 10 damage per hit on ensnared Survivors and takes 5 seconds to ensnare a Survivor.
 * The Hunter does 6 damage per hit and 5 per hit on pounced Survivors.
 * The Charger does 5 damage in a punch, 10 damage when its target reaches a wall, and 15 damage per slam.
 * The Jockey does 3 damage while riding a Survivor.
 * The Spitter's spit acid's average damage is 31 and the body acid's average damage is 32.

Normal
Normal mode is fairly balanced, as far as the difficulties go. It's harder than easy, but not something that will quickly decimate an inexperienced player, such as in advanced or expert.

Normal is also the set difficulty for Versus mode.

Details

 * The Tank has 4000 health points, does 24 damage per hit and 75 when pounding.
 * The Witch has 1000 health points and is startled in 5 seconds.
 * Friendly fire inflicts 10% of the weapon's damage per hit to the Survivors.
 * Common Infected inflict 2 damage per hit in the front, and 1 from the back.
 * The Smoker does 10(3 while dragging and 6 when it finishes dragging on Versus) damage per hit on ensnared Survivors.
 * The Hunter does 10(6 in Versus) damage per hit and 5 per hit on pounced Survivors.
 * The Charger does 10 damage in a punch, 10 damage when its target reaches a wall, and 15 damage per slam.
 * The Jockey does 3 damage while riding a Survivor.
 * The Spitter's spit acid's average damage is 68, and the body acid's average damage is 69.

Advanced
Advanced is for more experienced players. Although it's not as devastating as Expert, it demands a high level of competency and care. If the player is not careful, then they should be ready for multiple tries per map, as things can get pretty hard — and friendly fire incidents are the bane of a serious player, as they take off quite a bit of health here. The fact that first aid kits don't spawn very often only serve to further exacerbate the problem.

Details

 * The Tank has 6000 health points, does 33 damage per hit and 100 when pounding.
 * The Witch has 1000 health points and is startled in 5 seconds.
 * Non-headshots get no bonus damage
 * Common Infected inflict 5 damage per hit from the front, and 2.5 from the back.
 * Friendly fire inflicts 50% of the weapon's damage per hit to the Survivors.
 * The Smoker does 20 damage per hit on ensnared Survivors.
 * The Hunter does 20 damage per hit and 10 per hit on pounced Survivors.
 * The Charger does 15 damage in a punch, 15 damage when its target reaches a wall, and 15 damage per slam.
 * The Jockey does 6 damage while riding a Survivor.
 * The Spitter's spit acid's average damage is 68, and the body acid's average damage is 69.

Expert
Expert mode is, obviously, the toughest difficulty of the four. It is not at all recommended for the inexperienced or impatient, as it may take many tries for the player to complete a single chapter. In this mode, never fear death, and always be on the move. Standing still is an almost guaranteed way to get killed here. But then, even moving has its down sides. The player must be ready for anything, anticipate everything. However, they must remember that in the end, it is very likely that they will die. Though it can get incredibly frustrating at times, with practice and a great deal of patience, it is possible to get through. The Tank is the worst thing that could happen on Expert.

There are many unique nuisances in Expert difficulty that you won't see in the others.

The horde
The time between Panic Events in Expert mode is a lot shorter than in the other modes, with around four hordes in three minutes, and the size of the horde is bigger. On top of that, Boomers will constantly be sent at the Survivors(not as much on L4D2 Due to more Specials), vomiting and exploding all over them. This makes progressing somewhat difficult as they may be stuck within one area for long periods of time attempting to deal with the Infected.

Details
This is a mostly complete list, extracted in part from the exposed cvar interface. See console commands for information on the cvars.
 * The Witch has 1000 health points, can instantly kill a Survivor and is startled in 4 seconds. Witches can only be CR0WND with a headshot (on easier difficulties you can shoot her in other parts of her body and still 'CR0WN' her) from a pump shotgun or an Auto Shotgun. If Witches are avoided without being startled the Director ensures to continually spawn them in your path, sometimes spawning three or four per level if the player(s) manage to keep avoiding them.
 * The Tank has 8000 health points, deals 100 damage per hit and 150 when pounding.
 * Fire inflicts 40 damage per second to the Survivors.
 * Friendly fire inflicts full damage to the Survivors. Avoid friendly fire at all costs. One direct shot from a Pump Shotgun or Auto Shotgun will instantly incapacitate a teammate.
 * Common Infected inflict 20 damage per hit from the front, and 10 from the back.
 * First-aid kits are extremely rare on Expert outside of the safe room and before the finale (except for the Death Toll Finale, and in the Ambulance right outside of Mercy Hospital.); They are instead replaced by pain pills, which become surprisingly common.
 * The Smoker does 30 damage per hit on ensnared Survivors.
 * The Hunter does 40 damage per hit and 15 damage in half second (30 per second) on pounced Survivors.
 * The Charger does 20 damage in a punch, 20 damage when its target reaches a wall, and 15 damage per slam.
 * The Jockey does 9 damage while riding a Survivor.
 * The Spitter's spit acid's average damage is 68, and the body acid's average damage is 69.
 * At close range the Tank is extremely good at cutting off and closing in on Survivors who try and turn, even a little (By turning it any movement other than running directly away from him.) The only way to outrun a Tank on Expert at close range is to continue to run directly away from him. The same goes for his rock-throwing attack, it is absolutely unavoidable if you are not paying attention. The best way to avoid his rock throw attack is to continue to move in one direction while he prepares to throw the rock, then when he throws it change directions quickly. Or simply remain still and move at the right time.
 * The Boomer appears to have noticeably increased range with his vomit attack.
 * Enemy reactions are much faster; for example, Smokers will often pause for several seconds on easier difficulties before snaring you with his tongue; however, on Expert, they won't hesitate to attack again.
 * The most threatening Special Infected will almost always spawn on the path(s) you must take, namely the Tank and the Witch. However, observant players might notice a roaring, muscled or hunched, crying mass in the distance, and closed captions can help predict enemy locations, which can help a player get the drop on the Special Infected.
 * In Left 4 Dead 2, the Director will not only be sadistic, but is also creative in the ways it challenges the Survivors. For example, if a Wandering Witch is roaming around somewhere, and say you throw a pipe bomb to get rid of a horde, it will have the Witch move towards the pipe bomb, causing you to startle her and giving you no choice but to fight her.

Realism
Realism is meant for people who play frequently together online. It can be activated on any difficulty level and changes gameplay to become, like the name suggests, more realistic, or in the developers' words, "like in the movies".

Details

 * Only headshots are instant kills, and attacks on the torso or limbs cause much less damage than they would normally do. Direct hits with the Grenade Launcher and the Magnum are still one hit kills.
 * Realism removes the outlines that normally appear around teammates when there is an obstruction between one another. Similarly, outlines around weapons and items also do not appear unless close enough to grab them. (Items that would normally have blue outlines have no outlines, making it harder to notice a lesser Tier weapon as well.) Outlines around Special Infected, such as a Hunter that pounced a Survivor, are also removed. This makes it particularly difficult for players to keep track of each other, and friendly fire will be much more difficult to avoid.
 * You do not respawn in closets so if you die, you must either wait until the next chapter or be revived via a Defibrillator.
 * Witches will kill any Survivor they attack, regardless of the difficulty; hence, The Sugar Mill requires extreme caution on Realism.
 * Contrary to popular belief, players can be incapacitated twice.

Some possible strategies to cope with the increased difficulty is to have at least one player carrying a defibrillator along, and consider killing all members below 50 HP in the safe room so that they will respawn with 50 HP in the next map. Players might also find it useful to bind their keys to vocalize commands or use the microphone to inform each other if they are in trouble.