Mutators in Duke Nukem Forever Multiplayer are weapon options available for multiplayer games. They can be chosen by the host when setting up a game and can be used with any gamemode (besides Freeze Tag, where only options are None or Infinite Ammo). The available mutators are:
- None - default setting. All the powerups and weapons have the set locations on map and can be picked up with their full ammo counter and the ammunition is limited. Duke has to reload the weapons that have limited clips (Pistol, Shotgun, Ripper, Railgun and Garter pistol, which has limited clips, but infinite total ammo count).
- Infinite Ammo - all the weapons have unlimited ammo counts and the weapons that normally would reloading don't need it anymore. Also picking up a single Pipe Bomb or Tripmine gives unlimited amount of those, however, still only 4 of each can be thrown/placed in the world at the same time. Main disadvantage of this mode is making some weapons unbalanced compared to normal game, mostly pipebombs and Enforcer Gun that can be spammed randomly and pistol which is very deadly without its main drawback (that being the need to reload often).
- Shotguns only - players are by default equipped with shotguns and all the normal weapon pickups change to shotguns. They have limited ammo and still need to be reloaded. Tripmines and pipe bombs, however, can still be found in their usual locations. Also all the powerups spawn normally. Player carrying the babe will still be equipped with Garter Pistol.
- Instagib - players are by default equipped with railguns with unlimited ammunition and no need to reload. No weapons or powerups but Jetpack (and Beer in HTTK modes) spawn on the maps. It should also be noted that even shrunk (by shrink pads) players can kill normal sized players with one shot, so campers often abuse it by getting shrunk purposely so they are harder to aim at. Player carrying the babe will still be equipped with Garter Pistol.
- Heavy weapons - players are by default equipped with shotguns, but the only weapons available for pickup are RPG, Devastator and Enforcer Gun as well as tripmines and pipe bombs. The ammo count is limited and there are no powerups but jetpacks and beer available. The normal weapon pickups will change as follows: Ripper and Freeze Ray into devastator, Shrinker, Shotgun and Expander into RPG and Railgun, AT Laser and Impregnader into enforcer gun. N00b T00b, DFG and Tittyana are normally available in their respective maps. Player carrying the babe will still be equipped with Garter Pistol.
- Knuckle Sandwitch - Duke is only equipped with his bare hands and all he can find on maps are pipe bombs and tripmines. The only available powerup is jetpack. Also normal weapon pickups will turn into two pipe bombs (Shotgun, RPG, Railgun, Shrinker, Enforcer Gun) or two tripmines (ripper, devastator, AT laser, freeze ray). All the DLC weapons turn into one pipe bomb and one tripmine. Player carrying the babe will still be equipped with Garter Pistol.