Eighty-five patients with thalassemia and all available immediate family members were typed for HLA-A,B, C, and DR antigens, and the patients were tested for clinical diabetes and white cell antibodies in response to multiple blood transfusions. The antigen Bw35 was increased among both patients and their parents. This finding is consistent with previous data suggesting that this antigen may offer an independent selective advantage in populations at risk for both thalassemia and malaria. No association of the HLA system to the development of diabetes was noted. A wide variation was observed in the degree of white cell antibody response to transfusions: 25 of the 84 patients tested had significant levels of white cell antibodies while the majority (49) of the patients had essentially no antibodies. The frequency of the antigen DR2 was significantly increased in the high-response group, while the antigens Bw35 and DR7 were significantly increased in the low-response group. This finding suggests that an HLA-linked immune response or immune suppression factor or an HLA-linked susceptibility to iron toxicity may play a role in the development of these antibody responses.