Comisso was born into a middle-class family in Treviso in northern Italy. In 1914, at age 19, he volutereed for the army even before Italy had officially entered the war. He published his first poems, strongly influenced by Baudelaire, Rimbaud and Nietzche, in pamphlet form in 1916.

After the end of the war Comisso briefly attended university in Rome. Between 1921 and 1924 he attended university in Genoa, Padua, and Siena graduating in Letters. He spent the next nine years earning a living as a freelance journalist. In 1933 Comisso choose to settle near his native Treviso, where he lived simply, grew his own food and wrote. It was also during these early settled years that he had his most significant relationships.

The first was with a 16-year-old boy, Bruno Pagan. Their love affair lasted to 1937, when Bruno went his own way. Three years later Comisso took in anoter 16-year-old boy, Guido Bottegal. Towarsd the end of the WWII Bottegal was mistaken for a fascist spy and executed by partisans. Comisso never got over his death.

In 1956 Comisso built a new house closer to Treviso, and employed a secretary-chauffeur. But the new man was middle-aged, and did not take the place formerly occupied by Pagan and then Bottegal. In fact Comisso adopted his illegitimate children. He continued to write novels, which were enjoyed by a select public and well regarded by critics, until shortly before his death.