The beautiful Italian actress, 48, and French actor, 46, broke the news in a statement released to France's national news agency, Agence France-Presse, saying that the couple are separating by "mutual agreement."
Vincent's spokesman told AFP that "Vincent Cassel confirms that he has agreed to separate from his wife Monica Bellucci."
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The pair, who were married for 14 years and together for 18, met on set of Gilles Mimouni's French-language film The Apartment in 1996.
They wed several years later in a quiet ceremony in Monaco, on the French Riviera, and went on to have two daughters together, Deva, seven, and three-year-old Leonie.
Earlier this year, Monica, who has starred in films such as The Matrix Reloaded and Mel Gibson's The Passion of the Christ, told Grazia magazine: "Marriage, we never know how long it will last...Today, it works, but in a year, I don't know."
The former model has also opened up about fidelity in the past. She told The London Times that "confidence, respect" and "knowing a man will be there for you is more important than just fidelity."
Monica and Vincent pose during a photocall for Irreversible during the 55th Cannes Film Festival
Popular French actor Vincent and Monica, who was born in Italy, had been leading independent lives for some time, keeping their own respective apartments in Paris and Rome.
Vincent is known to American audiences for his work in Black Swan, Eastern Promises, The Messenger, Elizabeth and Ocean's Twelve and Ocean's Thirteen.
He has also starred in many French-language films, including La Haine (Hate) and Irreversible, in which he worked alongside his wife. The controversial 2002 film was released in the US in 2003.