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Born in La Spezia, Italy, Giannini studied at the Academia Nazionale in Rome, and made his film debut in a small part in Fango sulla metropolis in 1965. He appeared in supporting roles in Anzio and The Secret of Santa Vittoria, and starred in the original version of Swept Away.
In 1976, he starred in Seven Beauties, for which he was nominated for the Academy Award for Best Actor, which is unusual in that his performance was given entirely in Italian. He dubbed Jack Nicholson's voice in the Italian release of The Shining, for which Nicholson sent him congratulations. He also starred in Hannibal.
Giannini's best-known starring roles have been in films directed by Lina Wertmuller: in addition to Swept Away and Seven Beauties, he also appeared in The Seduction of Mimi, Love and Anarchy, A Night Full of Rain, and Francesca e Nunziata.