OBJECTIVE: The goal of this study was to identify in human immunodeficiency virus (HIV)-infected individuals immunologic markers that correlated with transmission of HIV by heterosexual contact. METHODS: In a case-control comparison of couples, immunologic and viral parameters were evaluated in 343 HIV-positive individuals who were members of 67 HIV-seroconcordant couples (both partners HIV positive) and 211 HIV serodiscordant couples (one positive, one negative). RESULTS: The most striking immunologic finding was the increased numbers of CD3+CD8+ cells found in the index member of discordant couples as compared to the index member of the concordant couples. Differences in CD3+CD8+ levels persisted after adjustment for stage of disease and CD3+CD4+ count. This increase in the number of CD3+CD8+ cells was accompanied by a concomitant decrease in the amount of viral replication measured by both HIV culture endpoint and quantitative RNA polymerase chain reaction (PCR). CONCLUSION: Data presented here further support the role of CD3+CD8+ cells in suppressing or controlling viral activity, although a causal role based on case-control data must be advanced cautiously. This in vivo biologic function may help prevent or lower the risk of HIV transmission.