Application of sensitive radioimmunoassays for the detection of hepatitis A and B viruses has demonstrated that up to 25% of cases of acute sporadic hepatitis and up to 90% of cases of posttransfusion hepatitis cannot be classified by etiologic agent and warrant designation as non-A, non-B hepatitis. Epidemiologic studies have indicated a pattern of transmission similar to that of hepatitis B virus, with predominance of parenteral routes of spread. Spontaneous resolution of acute infection fails to occur in up to 60% of patients; a chronic asymptomatic but infectious carrier state is recognized. Although the chronic hepatitis is usually mild, a potential for progression to cirrhosis has been described. Transmission studies in chimpanzees have suggested the existence of at least two non-A, non-B agents, which produce strain-specific ultrastructural changes in the hepatocyte and confer a homologous immunity. Multiple assay systems for detecting putative viral antigens have been developed, but their specificity has not been confirmed. Elimination of blood procured by contract from commercial blood banks diminishes the risk of posttransfusion hepatitis and is recommended for prophylaxis. Although the effectiveness of immune serum globulin in the prevention of sporadic disease has not been established, its administration should be considered after exposure to incriminated blood, in spouses during the acute illness, and in neonates of infected mothers.