The Holsom twins die when alien babies burst out of their bodies. Inside, he finds swarms of Octabrains and the missing women, who have been impregnated with alien spawn. Duke uses a wrecking ball to plow his way into the Duke Dome. He also warns Duke that the aliens are using the Hoover Dam to power a wormhole so that more aliens can come to Earth. Graves tells Duke that the women are being held in the Duke Dome and that the aliens have a vendetta to settle with Duke. While fighting through his Las Vegas casino, Duke witnesses the aliens abducting women, including his two pop-star girlfriends. Duke is forced to disobey the president's orders and fight his way through the alien hordes in an effort to save Earth. Before Duke can leave his chambers, he is attacked by hostile aliens. Duke obliges this request but remains uneasy. The president orders him not to harm the invaders, and he adds that he is in diplomatic talks with the alien overlord. There, he receives a call from the president and General Graves of the military. Duke's talk show appearance is cancelled to allow television stations to cover the alien invasion, so Duke retires to the Duke Cave. Unlike previous encounters, the aliens initially appear peaceful and at first seem to pose no harm to the humans of Earth.

On his way to the show, Duke witnesses a news broadcast on a nearby television screen announcing that aliens have once again invaded. The game begins with Duke sampling a video game based on his past heroics, followed by a scheduled interview with a talk show host. Duke Nukem is now a world-renowned icon, living in the penthouse of a Las Vegas casino with his casual partners, the Holsom twins. The events in Duke Nukem Forever take place about twelve years after the conclusion of Duke Nukem 3D.

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