In a selective epidemiologic study of Reye's syndrome (acute encephalopathy with fatty degeneration of the viscera) 62 cases were reported from parts of the United States and Puerto Rico over a 30-month period. Most of these cases were reported from a few areas where the diagnostic index of suspicion was high, suggesting that the overall national incidence may be considerably higher than has been generally appreciated. Several areas reported epidemic patterns in February and March 1969, concurrent with outbreaks of influenza B virus infection. Seven additional sporadic cases in the 30-month period were associated with chickenpox. Patterns of incidence of such viral infections may account for variations in incidence of Reye's syndrome beyond those attributable to differences in index of suspicion and case finding. Epidemiologic data do not support an etiologic role for exogenous toxins or medications. An inverse relationship between the manifestation of hypoglycemia or hypoglycorrhachia and age of patient was demonstrated. The growing evidence found associating Reye's syndrome with infection by common viral agents, such as influenza B, suggests a potential role for immuno- or chemo-prophylaxis.