It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospecti vely studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1—specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P = .03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Δ32/Δ32). Median plasma HIV-1 RNA levels from 18 HIV-1—infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Δ32 CCR5 mutation does not account for the majority of persistently HIV-1—resistant cases, and the presence of cellular immunity in these persons suggests either undetected infection or protective immunity.