The submarine departed from Malta on her last patrol, on 23 December 1942 under the command of Lieutenant M.E. Faber. She was sunk with the loss of her entire crew two days later whilst attacking an Italian convoy in the Gulf of Tunis heading towards Tunis. The submarine was depth charged by two Italian torpedo boats, Ardente and Ardito, at position 37º15'N, 10º30'E, northwest of the island of Zembra. The submarine was officially declared overdue on 5 January 1943.
This vessel and her crew were honored and immortalized by the nephew of one of the lost sailors (Lt. Stephen E. Spring Rice, RNVR), English musician Thomas Dolby, in the song "One of Our Submarines".