The histopathology of fatal Venezuelan equine encephalitis (VEE) in humans has not been well documented. To evaluate the spectrum of disease in man, the histologic slides of the 21 autopsied patients who died with documented VEE infection during the 1962–63 VEE epidemic in Zulia, Venezuela were reviewed. The main histopathologic lesion observed in multiple organs and tissues, especially the brain, gastrointestinal tract, and lungs, was moderate to marked diffuse congestion and edema with hemorrhage. In the central nervous system (CNS), mild or focal mixed inflammatory cell infiltrates were present in the leptomeninges and perivascular spaces (65%). Meningoencephalitis associated with intense necrotizing vasculitis was observed in 2 patients (10%), and cerebritis was observed in 5 cases (25%). There was a striking depletion of lymphocytes with vascular thrombosis and necrosis of follicles in lymph nodes (77%), spleen (69%), and the gastrointestinal tract (90%). Widespread hepatocellular degeneration and individual cell necrosis was observed in 61% of the cases. Most patients (90%) had interstitial pneumonia, frequently complicated by acute bronchopneumonia (33%). Overall, the lesions observed in the CNS and reticuloendothelial tissues are comparable to what is observed in experimental animals; however, extensive hepatocellular degeneration and interstitial pneumonia are not prominent pathologic features of VEE in animals. The findings are consistent with the hypothesis that lymphoid and reticuloendothelial tissues are the targets in VEE virus infection in humans, and that many of the histopathologic changes are attributable to primary lymphoid and endothelial cell injury.