Barry Wetcher/eOne Films

Steven Soderbergh swears he’s getting out of the business. After he completes his Liberace biopic, Behind the Candelabra—which features a scene of Michael Douglas as Liberace making out with Matt Damon as his lover—the director, who just turned 50, has vowed to retire from movie-making, and focus on directing plays and painting. It’s hard to imagine. There isn’t a major filmmaker in America more prolific, or provocative, than Soderbergh. In the past two years alone, he’s made four movies, a diverse suite that includes a disaster flick (Contagion), an action picture (Haywire), and a $7-million story of a male stripper that grossed $167 million (Magic Mike). His latest film, Side Effects, is a thriller that poses as a cautionary tale about pharmaceutical drugs, then derails expectations with such diabolical mischief you can almost smell the filmmaker’s impatience with convention.

Soderbergh is Hollywood’s most successful misfit. For all his success as both a director and producer, he still hasn’t found a comfort zone. In an interview in New York magazine, he expresses mounting frustration with “the tyranny of narrative . . . or at least narrative as we’re currently defining it.” He says, “I’m convinced there’s new grammar out there somewhere.” He also complains that “the audience for the kinds of movies I grew up liking has migrated to television.” In fact, after no Hollywood studio would risk $5 million on distributing his Liberace movie (which he describes as “pretty gay”), he took it to HBO, the promised land for filmmakers aching to break out of the Hollywood straitjacket.

In Side Effects, Soderbergh casts Rooney Mara, that Girl with the Dragon Tattoo, as a girl with a lethal prescription in a thriller so perversely deceptive it should come with a list of side effects all its own. The movie’s time-release narrative is a jagged little pill of retro noir, coated with a smooth, contemporary glaze of pharma politics. Emily (Mara) and Martin (Channing Tatum), a New York couple who once owned a yacht and a mansion, are struggling to rebuild their lives after Martin comes home from a four-year prison term for insider trading. A suicide attempt leaves Emily in the care of a shrink (Jude Law), who puts her on a new anti-anxiety drug called Ablixa. As her former psychiatrist (Catherine Zeta-Jones) enters the picture, lies are unravelled and we’re pulled down a very different rabbit hole from the one we signed up for.

At the heart of each characer is a haze of moral ambiguity—something Hollywood abhors and Soderbergh adores. He seems to delight in aiming curveballs at his audience. But then this is a director who made his name by breaking the rules. He was just 26 when he won the Palme D’Or in Cannes with the first of his 26 features, Sex, Lies and Videotape, a brazen feat of minimalist style that helped launch a new wave of American indie cinema. He’s since won an Oscar for Traffic, which he accepted with barely a flicker of emotion. He turned George Clooney into a movie star, by stubbornly casting him until the notion stuck. And he has mastered the art-commerce shuffle, switching between studio blockbusters, like the Ocean’s Eleven franchise, and experiments on film’s wild frontier—such as casting porn star Sasha Grey as a high-priced hooker in the Godard-like verité of The Girfriend Experience (2009).

In the spirit of Godard, Soderbergh toggles between stylistic subversion and political expression. His “issue” movies range from whistleblower dramas (Erin Brockovich, The Informant!) to his Communist opus, Che. But all his films are inflected with dissent. And in a movie culture that thrives on lush sentiment, Soderbergh frames stories with a clinical, dispassionate eye—literally, given that he serves as his own cinematographer.

Along the way, he has built a cohort of loyal actors, notably Douglas and Damon, who agreed to take the plunge as gay lovers in the Liberace film. “It was great to see Michael and Matt jump off the cliff together. They just went for it,” says the director, apparently content to finesse his career with another end game of truth or dare.