Benacerraf, who was born in the Venezuelan capital of Caracas, was brought up in France but moved to America in 1940, becoming naturalized in 1943. He studied at Columbia and the University of Virginia where he obtained his MD in 1945. He worked first at the Columbia Medical School before spending the period 1950–56 at the Hospital Broussais in Paris. He returned to America in 1956 to the New York Medical School where he served from 1960 to 1968 as professor of pathology. After a short period at the National Institute of Allergy and Infectious Diseases at Bethesda, Maryland, Benacerraf accepted the chair of comparative pathology at Harvard in 1970, a position he held until his retirement in 1991.

In the 1960s, working with guinea pigs, Benacerraf began to reveal some of the complex activity of the H2 system, described by George Snell. In particular he identified the Ir (immune response) genes of the H2 segment as playing a crucial role in the immune system. This was achieved by injecting simple, synthetic, and controllable ‘antigens’ into his experimental animals and noting that some strains responded immunologically while others were quite tolerant. Such differential responses have so far indicated there are over 30 Ir genes in the H2 complex.

Later work began to show how virtually all responses of the immune system, whether to grafts, tumor cells, bacteria, or viruses, are under the control of the H2 region. Benacerraf and his colleagues continued to explore its genetic and immunologic properties and also to extend their work to the analogous HLA system in humans. This work may well be important in the study of certain diseases, such as multiple sclerosis and ankylosing spondylitis, which have been shown to entail defective immune responses.

In 1980 Benacerraf was awarded for this work, together with George Snell and Jean Dausset, the Nobel Prize for physiology or medicine.