Abstract Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to CTL. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplotype) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized cofactors of infection, including age and GUI. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission.