Apoptosis of neurons and glial cells has been shown to occur in the brain of patients with the acquired immune deficiency syndrome (AIDS) and was postulated as contributing to brain atrophy and white matter damage in these patients. Since apoptotic events may be induced by the Fas-Fas ligand (FasL) system, we analyzed the relevance of these molecules to cell depletion in eight brains from HIV-1-infected patients and nine HIV-1-negative controls all of whom were analyzed histopathologically. The presence of Fas and FasL in brain tissue was analyzed by PCR amplification using Fas- and FasL-specific oligonucleotide primers and immunohistochemistry. The visualization of DNA fragmentation was used to evaluate apoptosis. Fas transcripts were detected in brains from each of four AIDS patients, each of three asymptomatic HIV-1 carriers and each of two HIV-1-negative controls. In the brains from AIDS patients the level of Fas expression was higher than in asymptomatic carriers and uninfected controls. FasL transcripts were seen in three of seven HIV-1-infected brains, two AIDS cases and one asymptomatic HIV-1 carrier. The predominant Fas-expressing cells were reactive astrocytes seen in each of two AIDS patients and one pre-AIDS case, but not in HIV-1-negative controls. Occasional Fas-positive oligodendrocyte-like cells were also seen in AIDS and pre-AIDS cases. No significant expression of Fas and FasL was seen in neurons. Fas-positive reactive astrocytes were more frequent in foci of HIV-1 encephalitis (HIVE). In the same area reactive apoptotic astrocytes were seen in close vicinity to FasL-expressing CD3 T lymphocytes, suggesting that apoptosis of astrocytes is mediated by Fas-FasL. The Fas expression on glial cells in asymptomatic HIV-1 infection may indicate apoptosis already in the asymptomatic stage of HIV-1 disease. In AIDS brains expression of Fas and FasL may contribute to the loss of glial cells and indirectly to the loss of neurons.