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Born in 1964 in the Italian village of Citta di Castello, Umbria, Bellucci originally pursued a career in the legal profession. While attending the University of Perugia, she modeled on the side to earn money for school, and this led to her modeling career. In 1988, she moved to one of Europe's fashion centers, Milan, and joined Elite Model Management. Although enjoying great success as a model, she made her acting debut on TV in 1990, and her American film debut in 1992's Bram Stoker's Dracula (1992). Her role in the 1996 French thriller, Appartement, L' (1996), shot her to stardom as she won the French equivalent of an Oscar nomination.

In 2000, Bellucci returned to Hollywood to play Gene Hackman's estranged trophy wife in Under Suspicion. The film's director, Stephen Hopkins, had seen L'Appartement on a transatlantic flight and requested that she star in the thriller. That same year, the actress earned unprecedented worldwide acclaim for her performance as the title character in Malèna. Helmed by award-winning director Giuseppe Tornatore, the film featured Bellucci as a quiet young bride who is left alone in a small Sicilian town when her husband goes off to fight in World War II. Stunningly attractive, she struggles to keep her dignity as she is spurned by the female villagers and preyed upon by the men. Bellucci followed up Malèna's success with another international hit, Christophe Gans' genre hybrid Le Pacte des Loups (Brotherhood of the Wolf) (2002). The stylish cross between period piece and kung-fu flick (which also starred Cassel) was the fourth most successful film of its year in France. After conquering Europe, the film became an art house hit in the States and Bellucci received a nomination for Best Supporting Actress from the U.S. Academy of Science Fiction, Fantasy, and Horror Films.

The subject of numerous fan sites and men's magazine articles, Bellucci went on to star as the seductive Queen of the Nile in the comic book adaptation Astérix Obélisk: Mission Cléopâtre. In 2001, she joined Dracula co-star Keanu Reeves in the cast of the highly anticipated follow-ups to The Matrix (1999), The Matrix Reloaded (2003) and The Matrix Revolutions (2003). Soon after, Bruce Willis personally chose Bellucci to play a humanitarian doctor whom he must save from war-torn Nigeria in Tears of the Sun, director Antoine Fuqua's follow-up to his hit Training Day (2001).

In 2004, Bellucci's momentum continued to build when she starred as Mary Magdalene in The Passion of the Christ, Mel Gibson's self-produced blockbuster retelling of the final 12 hours of Jesus Christ. In the wake of that film's success, Bellucci teamed with two other renowned directors, Terry Gilliam and Spike Lee, with roles in The Brothers Grimm and She Hate Me, respectively.