In mice, susceptibility to leukemia is closely linked to “Ia” antigens coded by the major histo-compatibility complex and is transmitted recessively. To test this hypothesis in man, 89 patients with acute leukemia were typed for the eight known HLA-DRw specificities, representing the human counterpart of the Ia system, and compared with a normal unrelated control population (n=123). Phenotypes showing only one identifiable DRw antigen were significantly increased in patients with acute leukemia. Within such phenotypes, there was a predominant and significant occurrence of DRw antigens 3, 6, and 7, depending on the type of leukemia (AML, ALL in adults, and ALL in children respectively). These findings are most probably due to an excess of homozygotes for these particular DRw antigens, thus suggesting a recessive mode of transmission of susceptibility to leukemia in man.