The PC version allows Duke to hold four weapons in the single-player campaign. Items that have an effect on Duke can be picked up by the player; these items are steroids, beer, and the holoduke. Steroids increase the strength of Duke's melee attacks by a great deal for a limited time. Beer makes Duke much more resistant to damage, but blurs the screen. The holoduke creates a hologram of Duke Nukem that looks and acts in a very similar way to Duke, but often says slightly twisted versions of his one-liners. While the holoduke is in effect, Duke becomes invisible and the AI characters do not recognize his presence. The jetpack also returns, but only in multiplayer.
Instead of the health system featured in the previous Duke Nukem games, in which health would be depleted when Duke was injured and would only increase upon finding a health pack, drinking water from fountains/broken fire hydrants, urinating, or using the portable medkit item, Duke Nukem Forever employs a system involving an "ego bar". The ego bar depletes when Duke is attacked; once it is fully depleted, Duke becomes susceptible to damage. Dying will result upon taking too much damage and cause the game to reload the last checkpoint. If the player avoids further damage, then the ego bar and Duke's health are restored. The player can increase the size of the ego bar (thus increasing the amount of damage Duke can take) by interacting with certain objects throughout the game (for example, a mirror), and by defeating bosses. The game employs a save system that is solely based on checkpoints.
Plot
Twelve years after he saved the Earth from an alien invasion, Duke Nukem is a worldwide icon, and has achieved great fame from his heroic deeds. After sampling a video game based on his past heroics (the game Duke plays is a revamped version of the final level of the third episode of Duke Nukem 3D), he arrives on the set of a talk show for an interview. On his way to the show, Duke witnesses a news broadcast announcing that aliens have once again invaded. Unlike previous encounters, the aliens initially appear peaceful and at first seem to pose no harm to the humans of Earth.
Duke's talk show appearance is cancelled to allow television stations to cover the alien invasion, and Duke retires to the "Duke Cave", his personal home. There, he receives a call from the President and General Graves of the Earth Defense Force (EDF). The President orders Duke not to harm the invaders, and adds that he is in diplomatic talks with the alien overlord. Duke obliges this request, but he and Graves remain uneasy about the whole situation from start. Before he can leave his chambers, he is attacked by hostile aliens who are swearing revenge on Duke.
Duke is forced to disobey the president's orders and fight his way through the alien hordes in an effort to save Earth. While fighting through his casino, Duke witnesses the aliens abducting women, including his two live-in pop star girlfriends. Graves tells Duke that the women are being held in the Duke Dome, and that the aliens have a vendetta to settle with Duke. He also warns Duke that the aliens are using the Hoover Dam to power a wormhole so more aliens can come through. Duke travels to the Duke Dome, using a wrecking ball to damage the building to gain access. Inside, he finds swarms of Octabrains and the missing women, who have been impregnated with alien spawn; Duke's girlfriends die after giving "birth" to alien babies, infuriating Duke. Duke finds the Alien Queen in control of the Duke Dome and kills her, but is wounded in the process and blacks out.
After regaining consciousness, Duke fights Pigcops and aliens in through the Duke Burger. Soon, he travels to the Hoover Dam in his monster truck; after battling through the dam, he finds his old friend Dylan, mortally wounded. He tells Duke that the reborn Cycloid Emperor is at the dam, and that the only way to shut down the portal is to completely destroy the dam. Before dying, he gives Duke his demolition charges and wishes him luck. Duke places the explosives and destroys the dam, but the currents nearly drown him.
Duke is revived by an EDF soldier, and awakens to find the portal gone. The President, who was also at the dam, rages at Duke for ruining his plans to work with the Cycloid Emperor, revealing that the President was actually intending to have the aliens kill Duke and he would cooperate with Cycloid Emperor so he could control the Earth, and that he has ordered a nuclear strike at the site of the dam to wipe out the remaining aliens, intending to leave Duke there to die as revenge for foiling his plans. The Cycloid Emperor emerges and kills the President and his security detail, revealing that he intended to kill the President after the deal. Duke kills the Cycloid Emperor and is rescued by Graves just as the nuclear bomb explodes.
The game ends with a satellite surveying the detonation area and listing Duke Nukem as killed in action, to which Duke replies off-screen, "What kind of shit ending is that? I ain't dead. I'm coming back for more!" In a post-credits scene, a short video depicts a press conference, where Duke announces his intent to run for the 69th President of the United States.
