When Erik Stifler realizes that he's the only Stifler family member who might graduate high school a virgin, he decides to live up to his legacy. After some well-meaning advice from Jim's dad, Erik's ready to take his chances at the annual and infamous Naked Mile race, where his devoted friends and some uninhibited sorority girls will create the most outrageous weekend ever.

Romeo Montague is the alias of (the re-animated) Patient Zero, a skilled, mutated android hit-man/pimp/ancient relics collector, that lives in Verona City, N.Y.; a dystopic metropolis filled with extreme horror & sexual deviancy; featuring: a lustful, demonic, man-eating Astro-Queen, a psychotic South American underworld god, human/android sex-slave party-girls, bloodthirsty zombies, vengeful deities and alien hooker vampire junkies/go-go girls. The cities are also plagued with murderous cybernetic 'goon' robots, that are constantly trying to take Montague's life, as he and his street hustling pal 'Tricky' tries to figure out which one of his jive-ass enemies are trying to kill him (as well as trying to stay one step ahead of 'The Man'). In the middle of this chaos, Romeo/Zero tries to find the thief of his ancient , multi-million dollar voodoo ring.

Ailing, egotistical and sexually perverted rock-star Bobby Barzell (who sold his soul for wealth and rock and roll stardom) awaits a liver transplant from a psychotic fugitive of the law; as a vengeful, demonic alien tries to collect a past debt.