Patients with human immunodeficiency virus infection may develop a dementing illness. Using both in vitro and in vivo models, we investigated the susceptibility of the hippocampal formation to the Tat protein of human immunodeficiency virus. We also determined the pattern of hippocampal injury in patients with human immunodeficiency virus encephalitis. Following exposure of hippocampal slices to Tat, marked susceptibility of CA3 region with relative insensitivity of the CA1/2 region was observed. Injection of Tat into different regions of the rat hippocampus produced similar neuronal loss in both CA3 region and the dentate gyrus. In animals administered Tat, lesions were dose-dependent and immunohistochemical staining showed marked gliosis and loss of microtubule associated protein-2 in the affected areas at 3 days post-injection. Interestingly, synaptophysin staining was relatively preserved. In hippocampal tissue from patients with human immunodeficiency virus encephalitis, loss of microtubule-associated protein-2 staining was reduced in the molecular layer of the dentate gyrus. The results of our experiments demonstrate a unique pattern of hippocampal injury in organotypic culture and rats exposed to Tat. Our observations that patients with human immunodeficiency virus reveal a similar pattern of damage suggests that Tat protein may be pathophysiological relevant in human immunodeficiency virus encephalitis.