The pathogenesis of Venezuelan equine encephalitis (VEE) virus infection was compared in intraperitoneally inoculated mice (n = 24, 6 to 8 weeks old) and hamsters (n = 9, 90-110 g) using histopathology and immunohistochemical localization of VEE virus antigen. Infected mice developed paralysis, and the majority died by 9 days after inoculation. In contrast, hamsters did not survive beyond 3 days after inoculation, and they did not develop any neurologic signs. VEE virus antigen, demonstrated by immunoperoxidase staining, and pathologic changes were present in extraneural organs of both mice and hamsters. There was more severe involvement in hamsters, particularly in Peyer's patches of the distal small intestine. There was a severe encephalomyelitis in mice, but pathologic changes were not well established in the brains of hamsters before death. VEE virus antigen was widespread in the central nervous system of both mice and hamsters. VEE virus was found to be highly neurotropic in hamsters and had a similar distribution in the brain as in mice, but hamsters died from their extraneural disease before major central nervous system disease developed.