Hamster hematopoietic and lymphatic organs were studied sequentially by light and electron microscopy following Venezuelan encephalitis virus inoculation. In addition to extensive marrow and splenic necrosis nearly transmural necrosis of the ileum in Peyer's patch areas, with concomitant bacterial overgrowth, was noted. Viruses were observed ultrastructurally in reticular cells of Peyer's patches. In addition, bacterial blood cultures, consistent with an enteric origin, were generally positive in late stages of the infection. Reticuloendothelial function, measured by clearance of colloidal carbon, was significantly depressed in Venezuelan encephalitis virus-infected hamsters. It is proposed that the acute death of hamsters infected with Venezuelan encephalitis virus may be determined by the development of an endotoxic shock syndrome mediated by the extensive ileal lesions, coupled with impaired reticuloendothelial detoxifying function.