La Malfa was born in Milan, the son of Ugo La Malfa, a long-time Italian political leader and minister.
La Malfa served as secretary of the Italian Republican Party from 1987 to 1993, when he stood down and was indicted to face trial over a corruption scandal. He returned to politics in 1994, and has since 2001 been president of the party. From 2001 to 2005 he was President of the Finances Commission of the Italian Chamber of Deputies. He was Italian minister for European Union Affairs from April 2005 until the elections of April 2006, when La Malfa's center-right coalition lost its majority; La Malfa was nonetheless elected to Parliament.