Acquired immunodeficiency syndrome (AIDS), which is caused by human immunodeficiency virus (HIV-1), involves the apoptotic destruction of lymphocytes and, in the context of AIDS-associated pathologies, of neurons and myocytes. Several proteins encoded by HIV-1 trigger apoptosis by inducing permeabilization of the mitochondrial membrane. Several nucleoside analogs used clinically in the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA) and/or increase the frequency of mtDNA mutations. These cause severe mitochondriopathy and might contribute to lipodystrophy, the complication associated with HIV-1 therapy. HIV-1 protease inhibitors can inhibit apoptosis at the mitochondrial level, which might help to alleviate lymphopenia. Thus, it appears that the pathogenesis of AIDS, and the pharmacological interventions and complications associated with this disease, affect the mitochondrial regulation of apoptosis, which, therefore, largely determines the outcome of HIV-1 infection.