HIV-infected individuals may progressively lose both HIV-specific and unrelated CTL responses despite the high number of circulating CD8+ T cells. In this study, we report that∼ 25% of HIV+ donors produced TGF-β 1 in response to stimulation with HIV proteins or peptides. The production of TGF-β 1 was sufficient to significantly reduce the IFN-γ response of CD8+ cells to both HIV and vaccinia virus proteins. Ab to TGF-β reversed the suppression. We found the source of the TGF-β 1 to be predominantly CD8+ cells. Different peptide pools stimulated TGF-β 1 and IFN-γ in the same individual. The TGF-β 1 secreting cells have distinct peptide specificity from the IFN-γ producing cells. This represents an important mechanism by which an HIV-specific response can nonspecifically suppress both HIV-specific and unrelated immune responses.