HLA-A, -B, -C, -DR, and -DQ antigen phenotypes were determined in 266 Caucasian homosexual men, 90 of whom were HIV-1 seronegative, 94 HIV-1 seropositive AIDS-free, and 82 with a diagnosis of AIDS [36 with Kaposi's sarcoma (KS), 34 with opportunistic infection (OI), and 12 with KS and OI]. No significant differences in HLA-A or -B antigen frequencies were found in any comparisons of these groups. However, in comparisons of seropositive AIDS-free men with the AIDS groups, HLA-Cw7 was increased in frequency in OI and HLA-DR1, -DRw 14, and -DQw 1 in KS. HLA-DR3 and -DQw3 frequencies were decreased in KS, and DRw53 was decreased in OI. In a cohort of 102 HIV seropositive individuals that were followed for a mean of 43 months, AIDS developed in HLA-DR 1 positive men more frequently than in individuals with other HLA-DR phenotypes (p = 0.02). These results demonstrate probable genetic differences between individuals developing KS and OI and indicate that the HLA-DR 1 phenotype is a risk factor in disease progression in human immunodeficiency virus (HlV)-infected individuals.