Crash also won for Original Screenplay and Film Editing.
Meanwhile, Brokeback Mountain, which went into the night with a leading eight nominations, won for Best Director for Ang Lee, Adapted Screenplay and Original Score.
In his acceptance speech, Lee thanked Annie Proulx, who wrote the short story that the movie was based on, and said he made the film for his father, who passed away shortly before Lee starting filming Brokeback.
Reese Witherspoon and Philip Seymour Hoffman, who both went into the show highly favored, won for Best Actress and Best Actor respectively. They each played real-life people in their films; singer-songwriter June Carter Cash in Walk the Line and author Truman Capote in the biopic Capote.
Witherspoon thanked costar Joaquin Phoenix who "put his heart and soul into the performance" playing Johnny Cash and also thanked "my wonderful husband (Ryan Phillippe) and two children – who should be going to bed."
During his speech, Hoffman said, "I'm overwhelmed. I'm really overwhelmed." He then encouraged people to congratulate his mother, who accompanied him to the show. "She brought up four kids alone and she deserves congratulations for that."
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"All right, so I'm not winning Director," joked Clooney, who was also nominated in the director and screenplay categories for Good Night, and Good Luck. He is the first person in Oscar history to get a nod for acting in one movie and directing another.
Upon accepting his award, Clooney said that "Oscar winner" now will always be attached to his name, along with "Sexiest Man Alive 1997."
First-time Oscar winner Weisz thanked her "luminous acting partner" Ralph Fiennes, as well as writer John le Carre, who wrote the "unflinching and angry" story about "people willing to risk their own lives to fight injustice."
Crowd favorite March of the Penguins won for Documentary, and its French filmmakers all carried fake stuffed penguins onstage to accept the award.
Before any awards were handed out, Hollywood's biggest night kicked off with a homage to past Oscar hosts, including Billy Crystal, Chris Rock, David Letterman, Whoopi Goldberg, and Steve Martin who all made brief appearances – and each declined invitations to host this year.
The actual host, Jon Stewart (who woke up in a dream sequence next to Halle Berry – and then Clooney) began the evening by poking fun at his own big-screen career – most notably his role as "the fourth male lead in Death to Smoochy." He also joked that singer Bjork, who once famously wore a swan dress to the awards show, couldn't make it because "she was trying on her Oscar dress and Dick Cheney shot her."
In the technical categories, King Kong took home Oscars for Visual Effects and Sound Mixing as well as Sound Editing, an award presented by Alias star Jennifer Garner, who tripped on her way to the podium then joked, "I do my own stunts."
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Wallace & Gromit in The Curse of the Were-Rabbit, was named the best Animated Feature, while Six Shooter won in the Short Film (Live Action) category.
In the music category, Hustle & Flow's "It's Hard Out Here for a Pimp," won for Original Song. The enthusiastic, and nearly unintelligible, acceptance speech by members of Three 6 Mafia was one of the highlights of the show.
Legendary director Robert Altman, who has been nominated for seven Oscars but has never won one, was presented with an honorary Oscar by veteran actresses Meryl Streep and Lily Tomlin, who star in his upcoming Prairie Home Companion.
Altman compared making films to building a sandcastle at the beach. You build it, then "watch the tide come in and the ocean just takes it away, but that sandcastle lives in your mind."