Why HIV-specific CD8⁺ T cells ultimately fail to clear or control HIV infection is not known. We show here that HIV-specific CD8⁺ T cells exhibit increased sensitivity to CD95/Fas-induced apoptosis. This apoptosis is 3-fold higher compared to CMV-specific CD8⁺ T cells from the same patients. HIV-specific CD8⁺ T cells express the CD45RA⁻CD62L⁻ but lack the CD45RA⁺CD62L⁻ T cell effector memory (T_EM) phenotype. This skewing is not found in CMV- and EBV-specific CD8⁺ T cells in HIV-infected individuals. CD95/Fas-induced apoptosis is much higher in the CD45RA⁻CD62L⁻ T_EM cells. However, cytotoxicity and IFNγ production by HIV-specific CD8⁺ T cells is not impaired. Our data suggest that the survival and differentiation of HIV-specific CD8⁺ T cells may be compromised by CD95/Fas apoptosis induced by FasL-expressing HIV-infected cells.