Infection by lentiviruses such as human immunodeficiency virus, Maedi-Visna virus and Caprine Arthritis Encephalitis Virus, is associated with a variety of neurological syndromes, but the mechanism by which the damage occurs to the nervous system is not known. The viruses do not infect neurons and so the neurotoxic actions must be mediated indirectly. Here we applied synthetic peptide analogues derived from basic regions of Maedi-Visna virus and human immunodeficiency virus transactivating protein, tat, to rat brain in vivo and found them to be potent neurotoxins. The toxicity of the Maedi-Visna virus peptide was demonstrated to be reduced by blockade of nitric oxide synthase and of N-methyl-D-aspartate channel opening. These experiments suggest that peptides derived from lentiviral tat may share a common neurotoxic action.