Cognitive and motor impairment are common symptoms among patients infected with the human immunodeficiency virus (HIV), including children who suffer neurological deficits and are frequently developmentally impaired. The HIV envelope protein, gp120, which has been shown to be toxic to neurons in culture, is shed in abundance by infected cells, and thus may play a significant role in the neuropathology of AIDS. To test this possible mechanism, neonatal rats were injected systemically with purified gp120 and the following consequences were observed: (1) radiolabeled gp120 and toxic fragments thereof were recovered in brain homogenates; (2) dystrophic changes were produced in pyramidal neurons of cerebral cortex; (3) retardation was evident in developmental milestones associated with complex motor behaviors. In parallel studies, co-treatment with peptide T, a gp120-derived peptide having a pentapeptide sequence homologous with vasoactive intestinal peptide, prevented or attenuated the morphological damage and behavioral delays associated with gp120 treatment. These studies suggest that gp120 and gp120-derived toxic fragments may contribute to the neurological and neuropsychiatric impairment related to HIV infection, and that peptide T appears to be effective in preventing gp120-associated neurotoxicity in developing rodents.