Scamarcio was born in Trani, Apulia, the son of Irene Petrafesa, a painter, and Emilio Scamarcio.
He went to train as an actor at the Scuola Nazionale di Cinema in Rome, where he now lives. His debut acting role was in a TV series in 2000, while his first ever lead role in a feature film was in Three Steps Over Heaven (2004), directed by Luca Lucini. Through this he immediately became well known to the Italian speaking public, especially a young audience. His success brought him prominence as a sex symbol and boosted requests for his acting skills, leading to his role in Texas (2005), directed by Fausto Paravidino and soon to him joining the cast of Romanzo Criminale, playing a monosyllabic, enigmatic thug character in a powerful portrait of a mafiosi community directed by Michele Placido.
In 2006 he acted in The Black Arrow, a TV series broadcast by Canale 5, adapted from the novel by Robert Louis Stevenson, and took on four new film roles: My Brother Is an Only Child (2007), directed by Daniele Luchetti, based on the novel Il fasciocomunista by Antonio Pennacchi. Scamarcio won a David di Donatello nomination for Best Supporting Actor for this work. He also played in Manual of Love 2 (2007), directed by Giovanni Veronesi, Ho voglia di te (2007), directed by Luis Prieto, and Go Go Tales (2007), directed by Abel Ferrara.

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