Musso was born in Rome and began his racing career driving sports cars before making his début on the Formula One circuit on 17 January 1954, driving a Maserati. In 1954 he won the Coppa Acerbo, a non-championship Formula One race. At Zandvoort, in the 1955 Dutch Grand Prix, Musso placed third in a Maserati. At the end of the 1955 Formula 1 season he switched to Ferrari. He shared victory in the 1956 Argentine Grand Prix with Juan Manuel Fangio, however his season was cut short after a crash in a sports car race at Nürburgring.
Musso triumphed in a Ferrari 3500 in the City of Buenos Aires sports car race on 20 January 1957. He was the third driver of the car. Stirling Moss finished second in a 'light powered' Maserati 3000. Moss made a last-ditch effort for his team at the end but came up short. A second Ferrari 3500, driven by Eugenio Castellotti, came in third. The Ferrari team gained eight points toward the 1957 World Championship in the event. The same year he won the Grand Prix de la Marne. Although the Marne was also not part of the Drivers' Championship, Musso nevertheless finished third in the overall standings for the season.
Musso was fatally injured during the 1958 French Grand Prix at Reims when his Ferrari hurtled off the course on the 10th lap of the 50 lap race. Running wide at the tricky Gueux Curve while chasing the leader, fellow Ferrari driver Mike Hawthorn, Musso's Ferrari struck a ditch and somersaulted. Musso was airlifted to hospital with critical head injuries and died later that day. Hawthorn went on to win the race.
Many years after Musso's death, Fiamma Breschi, Musso's girlfriend at the time of his death, revealed the nature of Musso's rivalry with fellow team Ferrari drivers Mike Hawthorn and Collins in a television documentary, The Secret Life of Enzo Ferrari. Breschi recalled that the antagonism between the Musso and the two English drivers, Mike Hawthorn and Peter Collins, encouraged all three to take more risks. She said: "The Englishmen (Hawthorn and Collins) had an agreement. Whichever of them won, they would share the winnings equally. It was the two of them against Luigi, who was not part of the agreement. Strength comes in numbers, and they were united against him. This antagonism was actually favourable rather than damaging to Ferrari. The faster the drivers went, the more likely it was that a Ferrari would win." Breschi related that at the time of his death, Musso was in debt, and thus winning the French Grand Prix (traditionally the largest monetary prize of the season) was all-important to him.
Within a year, Collins and Hawthorn were also dead, and Breschi could not suppress a feeling of release. "I had hated them both," she said, "first because I was aware of certain facts that were not right, and also because when I came out of the hospital and went back to the hotel, I found them in the square outside the hotel, laughing and playing a game of football with an empty beer-can. So when they died, too, it was liberating for me. Otherwise I would have had unpleasant feelings towards them for ever. This way I could find a sense of peace."
During his F1 career, Luigi Musso won one World Championship Grand Prix, achieved 7 podiums, and scored a total of 44 championship points.
(key) (Races in italics indicate fastest lap)
# Shared drive with Sergio Mantovani.
‡ Shared drive with Sergio Mantovani and Harry Schell.
* Shared drive with Juan Manuel Fangio.
† Crashed, later died of injuries.
(key) (Races in bold indicate pole position) (Races in italics indicate fastest lap)