Cuffaro was the son of Domenico Cuffaro, one of the founders of the Communist Party of Italy, leader of the Sicilian peasant and miners' movement and CGIL leader in the province of Agrigento.
After graduating in Naval and Mechanical Engineering with the highest grades, he moved to Aquileia, Friuli-Venezia Giulia. He assumed a chair of engineering at the "Alessandro Volta" Technical Institute in Trieste and worked as a consultant in the engineering field.
At that time Cuffaro joined the Italian Communist Party and in 1962 he was elected municipal councilor in Trieste. He was also elected regional councilor of Friuli-Venezia Giulia (1967–1976). In 1969 he joined the central committee of PCI, where he remained until 1991, the year of its dissolution.
He was Deputy for three legislatures from 1976 to 1987. From 1979 to 1988 he was also responsible for Scientific and Technological Research in the National Directorate of PCI. From 1977 to 1979 he took part in the work of the special chamber commission for the reconstruction of the areas of Friuli Venezia Giulia and the Veneto region affected by the 1976 earthquake.
Following the dissolution of PCI, Cuffaro joined the Communist Refoundation Party and in 1993 he ran for the party's secretariat, being defeated by Fausto Bertinotti. From 1994 to 1996 he served as a Member of the Senate.
On the occasion of the IV National Congress of PdCI, in 2007 he was unanimously elected President of the party replacing Armando Cossutta. He remained party's president until July 2013, when he was appointed Honorary President of the party.[2]