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At 18, Mezzogiorno enrolled at the university and began medical studies before choosing law. Then he had his first experience as an actor at the Teatro S. theatre where he recited texts by Samuel Beckett and Eugène Ionesco. Desiring to improve his diction he spent long nights exercising his voice with extracts of the Penal Code. In 1962, at age 21, he played Estragon in Waiting for Godot at the "Piccolo Teatro" of Naples.
In 1966 - 1967, he joined the troupe of Eduardo De Filippo and obtained his university diploma. In 1969, he met actress Cecilia Sacchi. Their collaboration quickly turned to a romantic relationship and they were married on 14 October 1972. On 9 November 1974 their only child Giovanna Mezzogiorno, who also became an actress, was born.
The family then settled in Rome where Mezzogiorno fully dedicated himself to the theatre.
In 1983 Jean-Jacques Beineix opened the doors of French cinema with Moon in the Gutter where he acted alongside Gérard Depardieu and Nastassja Kinski, but the real recognition came the same year in L'Homme blessé, a film by Patrice Chéreau, where he played Jean, a homosexual. Meanwhile, Mezzogiorno moved to Paris.
More than ten hours of entertainment, a year of rehearsals, six months of training in martial arts: the challenge of Peter Brooks Mahabharata, transcription of the long epic of Hindu mythology. Mezzogiorno was Arjuna, the son of Indra. It was first performed at the Boulbon Quarry in 1985 at the Festival d'Avignon and lasted all night. After a show at the Bouffes du Nord, it went on tour until the end of 1986 (Athens, Prato, Barcelona, Madrid and Lyon). The Mahabharata in English was back on the road in 1988: Zurich, Los Angeles, New York, Perth, Adelaide, Copenhagen, Glasgow, and finally Tokyo. In 1989, the movie adaptation was produced. In all, Mezzogiorno has played Arjuna for 6 years on 4 continents.
In 1990, Vittorio Mezzogiorno returned to Italy and settled in Milan. He became a star of the small screen by interpreting the Commissioner Davide Licata in the series La piovra which deals with the Mafia. In 1992 he played with his wife at the Teatro Stabile di Parma. This was to be his last appearances. He died of cancer in Milan at the age of 52.
- 1975 : La Cecilia by Jean-Louis Comolli
- 1976 : Basta che non si sappia in giro by Luigi Magni
- 1976 : La Orca, by Eriprando Visconti
- 1976 : Milano Violente by Mario Caiano
- 1977 : Stunt Squad, by Domenico Paolella
- 1979 : Il Giorni dei Cristalli by Giacomo Battiato
- 1979 : Il giocattolo by Giuliano Montaldo
- 1979 : Speed Cross by Stelvio Massi
- 1980 : Desideria: la vita interiore by Gianni Barcelloni
- 1980 : Cafè Express by Nanni Loy
- 1980 : Doppio sogno dei Sigg X, d'Anna Maria Tato
- 1980 : Car Crash by Antonio Margheriti
- 1980 : Arrivano i bersaglieri by Luigi Magni
- 1981 : La Caduta degli angeli ribelli by Marco Tullio Giordana
- 1981 : Three Brothers by Francesco Rosi
- 1981 : E noi non faremo karakiri by Francesco Longo
- 1982 : Un asila al Patibulo by Giuliana Berlinguer
- 1983 : La Casa del tapetto giallo, de Carlo Lizzani
- 1983 : L'Homme blessé, de Patrice Chéreau
- 1983 : Moon in the Gutter by Jean-Jacques Beineix
- 1984 : La Garce by Christine Pascal
- 1984 : Les Cavaliers de l'orage, by Gérard Vergez
- 1987 : Jenatsch by Daniel Schmid
- 1987 : Fuegos by Alfredo Arias
- 1988 : Contrainte par corps by Serge Leroy
- 1989 : La Révolution française by Robert Enrico
- 1989 : The Mahabharata by Peter Brook
- 1991 : Scream of Stone by Werner Herzog
- 1991 : The Conviction by Marco Bellochio
- 1991 : Riflesso in un cielo scuro by Salvatore Maira
- 1992 : Hors saison, by Daniel Schmid
- 1992 : Golem, the Spirit of the Exile by Amos Gitai
- 1990 Ciak d'Oro for Scream of Stone
- 1981 Nastro d'Argento for Tre Fratelli
- 1979 Nastro d'Argento for Il Giocattolo
- "Vittorio Mezzogiorno: l'homme blessé", par Alix de Saint André, Elle' mars 1983
- "En mémoire de Vittorio Mezzogiorno by Saverio Ferragina
- The Magic Baton: Toscanini's Life for Music, éditions Kessinger LLC, 2007