Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8⁺ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8⁺ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8⁺ T cells expressed a PD-1^high phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8⁺ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1^highCD8⁺ T cells produced IFN-γ, TNF-α, and IL-2 under cognate peptide stimulation. While CD8⁺ T cells that proliferated in response to antigen had a PD-1^high phenotype, it was determined that there was a reduced proliferative capacity of PD-1^high compared with PD-1^low SIV-specific CD8⁺ T cells. PD-1^high SIV-specific CD8⁺ T cells were highly susceptible to cell death leading to loss of such cells after in vitro stimulation. Thus, PD-1 is a negative regulator of SIV-specific CD8⁺ T cells, operating predominantly through the induction of cell death. Manipulation of the interaction of PD-1 with its ligands could thus potentially restore the CD8⁺ T-cell responses in SIV infection.