Apoptosis, a phenotype of programmed cell death involved in development and tissue homeostasis of multicellular organisms, brings into two major pathways and implies a central sensor: the mitochondria. Abnormalities in the cell death control can lead to a variety of diseases and many pathogenic agents target the mitochondria, especially affecting its permeability in order to induce cell death. HIV infection is linked to progressive CD4 T cell depletion. Among the different hypothesis that may explain T cell depletion, apoptosis is one of the main described mechanisms. This review provides current knowledge in HIV-mediated mitochondrial damage due to (i) HIV-specific proteins, (ii) death-by-neglect and (iii) side effects of the HIV drugs.