In its World Championship debut in the third round of the 1957 season, a 335 S (#531)(0676), driven by Spanish driver Alfonso de Portago (who had replaced an ill Luigi Musso) was in third place, running on a long straight road sector between the Lombard hamlets of Cerlongo and Guidizzolo when one of the tyres exploded.

Due to the crash only a single 335 S (0700) in the hands of Collins and Olivier Gendebien was entered in the next round at the Nürburgring 1000km and came second behind an Aston Martin DBR1 and although both 335 S models failed at Le Mans allowing the Jaguar D Types a 1-2-3-4 finish, Collins and Phil Hill obtained another second place in car 0700 at the Swedish GP behind a Maserati 450S with Mike Hawthorn and Luigi Musso finishing fourth in the sister car (0674).

A single 335 S (0700) in the hands of Olivier Gendebien finished third at Spa in the non-championship Grand Prix de RACB behind an Aston Martin DBR1 driven by Tony Brooks and a Ferrari 290 MM pilotted by Masten Gregory.

In the final round of the World Sports Car Championship at the Venezuelan Grand Prix, a 335 S (0700) raced by Collins and Phil Hill won with Hawthorn and Musso (0674) finishing second.

The change in regulations for the World Championship to a 3-litre engine limit which was a reaction to the Mille Miglia crash and earlier tragedies rendered the 335 S ineligible for the 1958 season onwards and Ferrari replaced the model with the 250 TR.