Apart from the unique changes characteristic of "HIV encephalitis", the productive infection of central nervous system by HIV, which predominantly involves the white matter and basal ganglia, evidence is accumulating that the cerebral cortex may also be affected in AIDS patients. Neuronal loss, suspected at microscopic examination, has been demonstrated by a number of morphometric studies. However, the cause and mechanism of neuronal damage in HIV infection, are still unclear. In an attempt to look for an apoptotic process at the origin of neuronal loss in AIDS, we examined samples of frontal cortex, temporal cortex and basal ganglia from 12 patients who died from AIDS and 4 asymptomatic HIV-positive cases using in situ end labelling to demonstrate characteristic DNA fragmentation. These were compared with 5 asymptomatic seronegative controls, and 2 seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in all AIDS cases and in the Alzheimer's cases. Positive in situ end labelling was usually associated with morphological changes suggestive of neuronal apoptosis. Semiquantitative assessment of the density of apoptotic neurons showed that neuronal apoptosis was more severe in atrophic brains. In contrast, no correlation was found between the density of apoptotic neurons and the presence of HIV-encephalitis or a history of cognitive disorder. Only occasional apoptotic neurons were found in one asymptomatic, HIV-positive case. Apoptosis was never observed in asymptomatic seronegative cases. We also looked for apoptotic neurons in spinal ganglia of 20 AIDS cases, 5 of whom had a terminal sensory distal neuropathy, and 10 seronegative controls devoid of neuropathy. Apoptotic neurons were found in 6 of the AIDS patients and in none of the seronegative controls. However, no correlation was found between the severity of neuronal apoptosis in the spinal root ganglia and the presence of absence of a terminal distal sensory neuropathy. Experimental studies tend to support our in vivo findings. HIV-infection of primary cultures of human embryonic central nervous system induced frequent apoptosis of neurons. No apoptotic cell was identified in non infected control cultures.