Mittelholzer wrote virtually nothing but fiction and earned his living by it. He is thus the first professional novelist to come out of the English-speaking Caribbean. Some of Mittelholzer's novels include characters and situations from a variety of places within the Caribbean. They range in time from the earliest period of European settlement to the present day and deal with a cross section of ethnic groups and social classes, not to mention subjects of historical, political, psychological, and moral interest. The difficulties he encountered in having his books published toward the end of his life affected Mittelholzer seriously. He was badly in need of money to support his first wife and children, as well as his second wife and son.

Mittelholzer took his own life near Farnham, Surrey, England, on May 5, 1965.