HIV-1 is associated with infection and altered functions of the CNS, especially in the elderly. Most studies indicate that HIV-1 is not evenly distributed throughout the CNS but is concentrated in deep brain nuclei. This study examined whether regional or age-related differences in the permeability of the blood-brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration of gp120 in 10 brain regions correlated with vascular content in young and old mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which relates to endothelial cell internalization, varied regionally, with no induction of uptake into the striatum or hypothalamus but with large increases in the cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the unidirectional influx rate (Ki), also varied regionally with the hypothalamus, hippocampus, and pons-medulla showing the highest values for Ki and the striatum the lowest. These regional variations in the permeability of the BBB to gp120 could contribute to the inhomogeneous distribution of HIV-1 within the CNS whereas the failure to see differences with aging suggests other causes underlie the susceptibility of the elderly to the CNS manifestations of AIDS.