Rotaviral infection is the most common cause of gastroenteritis in young children. Although rotavirus infection has a high morbidity and mortality rate in animals, in most cases in the United States the disease appears to be self-limited in humans. We report on 2 cases of fatal rotaviral infection in a 1 year old and a 4 year old. In each case, the illness showed a rapid systemic course dominated by cardiac and central nervous system involvement; in one case, rotaviral infection was documented by stool culture. Viral RNA was localized by reverse transcriptase in situ polymerase chain reaction to the mucosal cells of the small and large intestine and to many other tissues, including the heart and central nervous system, where it was noted in the endothelial cells of the microvasculature. Immunohistochemical analysis for the virus showed an identical histologic distribution in the intestinal epithelial cells and the systemic microvasculature. It is concluded that rotaviral infection can lead to a fatal disseminated infection in humans and the mechanism of this complication is based on a diffuse endothelialitis and concomitant tissue damage.