To examine the relationship of human leukocyte antigen (HLA) class I and transporter associated with antigen processing (TAP) genes with resistance to human immunodeficiency virus type 1 (HIV-1) infection, 100 HIV-seronegative men who had been exposed repeatedly to HIV-1 were compared with 184 men who had seroconverted to HIV positive and had lower risk. In the univariate analysis, the HLA-A2 supertype, excluding A*0201 (HLA-A2/6802 supertype; odds ratio [OR], 4.45; 95% confidence interval [CI], 1.33-4.84; P=.009) was associated with resistance to HIV-1 infection; the effect was the result of the presence of the A*0205 subgroup alleles. Susceptibility was associated in univariate analysis with the B*35 Px alleles (OR, 0.29; 95% CI, 0.08-0.99; P=.037), which suggests that differential preferences for amino acids at the C terminus may influence peptide-binding capacity. TAP2 Ala665 was also associated with resistance (OR, 2.26; 95% CI, 1.35-3.79; P=.002), perhaps because of its higher efficiency in transporting peptides, thus eliciting a greater CD8(+) T cell response, or because of linkage disequilibrium. In multivariate logistic analysis, only the A*0205 subgroup (OR, 5.56; 95% CI, 1.34-23.10; P=.018) and the TAP2 Ala665 (OR, 2.22; 95% CI, 1.28-3.84; P=.005) were associated with resistance.