Blood-brain barrier (BBB) disruption occurs during human immunodeficiency virus encephalopathy, but the mechanisms involved are not understood. We studied how acute and ongoing exposure to human immunodeficiency virus 1 envelope gp120 alters BBB structure and permeability. Intravenous Evans blue, given before stereotaxic gp120 injection into the caudate putamen of rats, was rapidly extravasated. Gelatinolytic activity, studied by in situ zymography, was increased after gp120 administration and was localized within cerebral vessel walls. The gp120 increased the expression of matrix metalloproteinases (MMPs) 2 and 9. Laminin and claudin-5, key BBB components and targets of both MMPs, were greatly reduced upon gp120 administration. The gp120 increased lipid peroxidation in the vascular endothelium and in neurons. Prior administration of rSV40 vectors carrying the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase protected from gp120-induced BBB damage. N-methyl-D-aspartate receptor activation upregulated pro-MMP-9 and increased MMP-9 gelatinase activity, and memantine, an N-methyl-D-aspartate receptor blocker, mitigated gp120-induced BBB abnormalities. Using intra-caudate putamen SV(gp120) to test the effects of chronic exposure to expressed gp120, we determined that oxidant stress and increased BBB permeability occurred as in acute exposure. These data indicate that both direct administration and cellular expression of gp120 lead to disruption of the BBB by increasing MMPs and reducing vascular tight junction proteins via mechanisms involving reactive oxygen species generation and oxidant injury.