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Genetic factors may play a role in the transmission of HIV-1. Because HLA-B alleles influence HIV-1 disease progression and viral levels, they might also influence HIV-1 transmission.To investigate if the presence of HLA-B alleles with the Bw4 epitope in HIV-1-infected men decreased the risk of transmission to their female sex partners.The study comprised 304 HIV-1-infected men with hemophilia and 325 female sex partners. HLA class I genes were amplified using sequence-specific primers. Products of the polymerase chain reaction were blotted on nylon membranes and hybridized with sequence-specific oligonucleotide probes. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for HIV-1 infection among the women.Among the 325 women, 44 (13.5%) were infected with HIV-1. HIV-1 infection in the women was associated with the HLA-B genotype of their male partner [Bw6/Bw6, 22/118 (18.6%); Bw4/Bw6, 18/154 (11.7%); Bw4/Bw4, 4/53 (7.6%)]. Compared with men who were homozygous for Bw6, men who carried Bw4 were about half as likely to have transmitted HIV-1 to their female partner (OR, 0.52; 95% CI, 0.27–0.98; P = 0.04). Transmission was higher among couples in which the man's ethnicity was other than White (OR, 2.60; 95% CI, 1.25–5.40; P = 0.01), but the association between HIV-1 transmission and HLA-B genotype was not confounded by race.The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission, which suggests that these alleles reduce infectivity for HIV-1.