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Lawyer and member of the French Section of the Workers' International (SFIO) political party, he was a member of the Brutus Network, a Resistance Socialist group during World War II. A long-standing member of the National Assembly (1945–1958, 1962–1986) and member of the Senate (1959–1962), he also served for many years as mayor of Marseille (1944–1945, 1953–1986). He was a formidable political force in the South-East, where he owned the major centre-left newspaper Le Provençal (which he co-founded at the Liberation) and later acquired the right-wing daily Le Méridional.
Defferre was Merchant Marine Minister (1950–1952) then Overseas Minister (1956–1957). He prepared the end of French colonialism in sub-Saharan Africa.
In his region, he faced a strong French Communist Party (PCF) with which he was frequently in conflict. As Mayor he relied on the support of the non-Gaullist center-right in the municipal assembly. In the same way, he advocated a national alliance between the SFIO and the Christian democratic Popular Republican Movement (MRP). Before the 1965 presidential election, L'Express published an identikit of the best center-left candidate under the name of "Mister X". It corresponded with Defferre's profile (L'Express co-founder Jean-Jacques Servan-Schreiber being a well known advocate of a Third Force alliance of socialists, Christian democrats and Radicals). But, failing to create an SFIO-MRP-Radical Party federation, he gave way to François Mitterrand, whose preferred strategy for the Socialists was the formation of a left-wing coalition including the PCF.
Defferre was the participant of the last duel in France that took place in 1967 when Defferre insulted René Ribière at the French parliament and was subsequently challenged to a duel fought with swords. René Ribière lost the duel, having been wounded twice. He escaped relatively uninjured, however. Defferre was the Socialist candidate in 1969 for the French presidency, with the support of ex-Premier Pierre Mendès-France, who would have been Premier again had Defferre been elected. But he was soundly defeated, suffering from the polarisation of French politics following the events of May 1968, scoring only 5% of the vote, the lowest ever score for a French Socialist candidate. The failure of Defferre prompted the birth of the new Socialist Party (PS) and buried the idea of an alliance with the centre-right.
Having been the main opponent of Guy Mollet in the party, and leader of the Socialist group in the National Assembly, Defferre helped François Mitterrand to take the leadership during the Epinay Congress (1971), in spite of Mitterrand's strategy of an alliance with the Communists. He later served as Mitterrand's Interior Minister from 1981 to 1984. He was the architect of the 1982 decentralization reforms. Town and Country Planning Minister until 1986, he died in office as Mayor of Marseille. His widow, Edmonde Charles-Roux, is president of the literary circle the Académie Goncourt.
- Secretary of State for Information : January–June 1946.
- Undersecretary of State for Overseas France : 1946-1947.
- Minister of Merchant Marine : 1950-1951 / March–August 1951.
- Minister of Overseas France : 1956-1957.
- Minister of State, Minister of Interior and Decentralization : 1981-1983.
- Minister of Interior and Decentralization : 1983-1984.
- Minister of State, Minister of Planning and Land Development : 1984-1986.
National Assembly of France
- Member of the National Assembly of France for Bouches-du-Rhône : 1945-1958 / 1962-1981 (Became minister in 1981) / March–May 1986 (He died in 1986). Elected in 1945, reelected in June 1946, November 1946, 1951, 1956, 1962, 1967, 1968, 1973, 1978, 1981, 1986.
Senate of France
- Senator of Bouches-du-Rhône : 1959-1962 (Reelected member of the National Assembly of France in 1962). Elected in 1959.
- Mayor of Marseille : 1944-1945 / 1953-1986 (He died in 1986). Reelected in 1953, 1959, 1965, 1971, 1977, 1983.
- Municipal councillor of Marseille : 1944-1945 / 1953-1986 (He died in 1986). Reelected in 1953, 1959, 1965, 1971, 1977, 1983.