Rap duo OutKast, featuring flamboyant Andre 3000 and Big Boi, grabbed three of the awards, including honors for best group, and best video and best song for "Hey Ya!"
Andre 3000, in a trademark red waistcoat and matching long socks, told the audience, "I hope you don't get tired of us. We only do what we do so see you next time."
Usher wasn't far behind. He captured two awards, including best male and best album for Confessions. Model Naomi Campbell, who has been linked to the singer, presented him with the best male award, smiling broadly and giggling as she read his name. Other winners of the night included Britney Spears for best female, Linkin Park for best rock act, and Alicia Keys for best R&B, among others.
Eminem kicked off the night's performances amid the sound of firing machine guns and helicopters. With a military tank as a backdrop, he performed his politically aware new single, "Mosh," accompanied by children dressed in fatigues.
The ceremony, which was beamed live to a potential one billion MTV viewers worldwide, had an old-and-new appeal. Majestic, historic Rome was juxtaposed with the modern world as the awards were held in a specially built tented structure at the city's Tor di Valle.
The Cure's Robert Smith introduced a "shimmering" Gwen Stefani who swung down to the stage suspended from a huge clock to perform her solo hit "What You Waiting For?" and other performers included the pork pie hat-wearing Beastie Boys and Scottish rockers Franz Ferdinand.
Among the other stars and celebrity presenters who turned out were Sarah Michelle Gellar, Duran Duran, AJ McLean and Nick Carter from the Backstreet Boys, and Sharon and Ozzy Osbourne.