Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system is associated with microglia activation and neuronal apoptosis, alterations that are also caused by the HIV-1 envelope glycoprotein 120 (gp120) alone. This study was undertaken to examine the onset of gp120 neurotoxicity, the type of cell death and which cells of the adult rat brain are more sensitive to the toxic action of gp120. Gp120 or vehicle were injected chronically (daily for 3 or 7 days) into the lateral ventricle. Magnetic resonance imaging revealed hypertensive areas in the cortical and hippocampal gray matter in gp120-treated rats 7-10 days after the first injection, suggesting vasogenic edema. This phenomenon was accompanied by an enlargement of the lateral and third ventricles. Immunohistochemical analyses were then carried out to examine the toxic effect of gp120 at a cellular level. Several markers of apoptosis, including activated caspase-3 were observed at both 3 and 7 days throughout brains of gp120-treated rats, especially in the cerebral cortex. In this area, most of the apoptotic cells exhibited a pyramidal shape and were Nissl positive, indicative of neurons. Few non-neuronal cells exhibited signs of apoptosis. The results of the present study support the notion that gp120 is neurotoxic in vivo and provide evidence that gp120 activates a caspase-dependent apoptotic pathway.