HIV-1 infects the brain and leads to AIDS dementia complex. The viral coat glycoprotein, gp120, may facilitate the passage of HIV-1 and HIV-infected immune cells across the blood-brain barrier (BBB). Since the endothelial cells of the BBB do not possess the CD4 or galactosylceramide binding sites used by gp120 to induce HIV-1 uptake into other cell types, how gp120 mediates entry into brain is unknown. We postulate that gp120 crosses the BBB and does so by acting as a weak lectin to induce adsorptive endocytosis (AE) in a fashion similar to other glycoproteins like wheatgerm agglutinin (WGA). We found in vivo that gp120 crosses the BBB and its passage is enhanced 18.7-fold by WGA. In vitro studies confirm that WGA enhances uptake of gp120 by brain endothelia; most of the uptake is membrane-associated, as expected in AE. Uptake is not dependent on clatharin, caveolae, calcium channels, or endosomal acidification. Our results suggest that gp120 crosses the BBB and does so by acting as a lectin to induce AE.