Cluzet grew up in Paris, and made his stage debut in 1976. Three years later, he made his premiere appearance on the big screen in Cocktail Molotov with Diane Kurys. A year later, Cluzet appeared in acclaimed family drama Cheval d'orgueil directed by Claude Chabrol. The two reunited in 1982 for Les Fantômes du chapelier. In 1983, Cluzet acted in L'Été meurtrier with Jean Becker. He was nominated for a César Award for best supporting role of the year, in the same year he made a list for best new male for film Vive la sociale.
Cluzet next collaborated with a number of major name French directors, all of whom had a predilection towards dramatic works: reuniting with Kurys in 1983 for Coup de foudre, reuniting with Bertrand Tavernier (to co-star in jazz film Round Midnight in 1985), Tony Gatlif (Rue du départ, 1985), Claire Denis (Chocolat, 1987), Pierre Jolivet (Force majeure, 1988, and one new César nomination for best second male role), Bertrand Blier (Trop belle pour toi, 1989) and again Robert Enrico (La Révolution française). Next, the actor worked with Claude Chabrol to play a husband tortured by jealousy in L'Enfer (1994) after having filmed with Chabrol in 1988 for Une affaire de femmes.
In 1994, Cluzet tried international cinema, acting in ensemble movie Prêt-à-Porter for director Robert Altman and romance French Kiss with Lawrence Kasdan. He returned to French cinema and comedy in 1995 with Les Apprentis (César nomination for best actor) and Enfants de salaud with Tonie Marshall, following a new Claude Chabrol: Rien ne va plus in 1997. Cluzet has often portrayed a role of the tormented writer: Fin août, début septembre with Olivier Assayas, L'Examen de minuit (1998), and Je suis un assassin (2004). He played the double of John Lennon in Janis et John (2003) and an animator of teleshopping in France Boutique (2004). In 2005, he played in Le Domaine perdu with Raoul Ruiz. The film portrayed the 1973 coup d'état in Chile.

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