Polymorphisms of genes in the human leukocyte antigen (HLA) complex, particularly those encoding HLA-DR, have been suggested as markers of susceptibility to Kaposi's sarcoma (KS). We conducted a case-control study comparing 147 homosexual men who developed KS after infection by human immunodeficiency virus-1 (HIV-1) and human herpes virus 8 (HHV8) with 147 matched dually infected men without HIV-associated KS (HIV-KS) from the Multicenter AIDS Cohort Study. HLA-B, DRB1, DRB3, DRB4, DRB5, and DQB1 polymorphisms were examined by high-resolution DNA-based methods. Differences in distributions of genetic variants were tested by conditional logistic regression. Previously reported relationships with HLA-DRB1 alleles could not be confirmed. Instead, other associations were observed. In univariate analysis, KS was weakly associated with B*2702/5 (odds ratio (OR) = 0.40, 95% confidence interval (CI) = 0.18-0.91). Similar or stronger associations, positive or negative, were seen for haplotypes containing class II alleles: DRB1*1302-DQB1*0604 (OR = 3.67, 95% CI = 1.02-13.1), DRB4 (DR53) haplotype family members [OR = 0.52, 95% CI = 0.32-0.85], and DRB3 (DR52) haplotype family members (OR = 1.69, 95% CI = 1.07-2.67). The B*1402-DRB1*0102 haplotype, which invariably contains the V281L mutation in the 21-hydroxylase gene governing adrenal steroid biosynthesis, occurred in five cases and one control (OR = 5.0, 95% CI = 0.58-42.8). In a final multivariable analysis, only DRB1*1302-DQB1*0604 (OR = 6.43, 95% CI = 1.28-32.3, P = 0.02) remained significantly associated with KS. Associations of HLA-DRB families with HIV-KS could reflect underlying immune dysregulation. The HLA B*1402-DRB1*0102 haplotype associated with increased risk of KS might represent an antigen-presenting pathway unfavorable for immune response to HHV8. Alternatively, the relationship might hold a clue to the predilection of KS for men because that haplotype harbors the mutant form of the 21-hydroxylase gene. © 2005 Wiley-Liss, Inc.