What governs the increased apoptosis sensitivity of HIV-specific CD8⁺ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8⁺ T cells from HIV⁺ patients and this could not be attributed to their different differentiation status. MM^High phenotype characterized those CD8⁺ T cells from HIV⁺ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38⁺ and CD38⁻ HIV-specific CD8⁺ T cells. Although CD38⁺ HIV-specific CD8⁺ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8⁺ T cells, as CD38⁻ HIV-specific CD8⁺ T cells were more apoptotic than CD38⁺ CMV-specific ones. Proapoptotic HIV-specific CD8⁺ T cells were CD38⁺Bcl-2^LowMM^High. Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8⁺ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8⁺ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8⁺ T cells.