Neuronal loss in HIV encephalopathy remains a mystery since HIV-1 productively infects macrophage and microglia and only rarely infects neurons in the central nervous system. Apoptosis is a mechanism which may account for the loss of neurons in HIV-1 infected brain. Putative toxic factors that result in neuronal cell death in HIV-1 infection include the regulatory protein Tat, since this protein is known to be released from HIV-1 infected cells. Here we show that Tat induces cell death by apoptosis in cultured human fetal neurons producing characteristic morphological and biochemical features associated with apoptosis. These findings suggest that Tat may play an important role as a secreted, soluble neurotoxin in HIV-1 associated dementia.