To supplement a detailed epidemiologic study of an outbreak of viral hepatitis in Venezuelan Indians in isolated valleys, apparently resulting from delta agent infection, 10 autopsy specimens were studied histologically and immunocytochemically, and five biopsy specimens were examined. The patients were children and young adults and predominantly males. A sequence of hepatitis from focal necrosis with conspicuous small-droplet steatosis, through massive necrosis, prolonged postnecrotic collapse to early cirrhosis with massive collapse was postulated. The histologic changes tentatively suggest a cytopathic effect of the delta agent without significant indication of lymphocytotoxicity, at least in the parenchyma. Delta agent was demonstrated in hepatocyte nuclei in moderate amounts in the focal-necrotic stage and in isolated cells in the massive-necrotic stage, but in large amounts during the transition to cirrhosis. Whether these patients, in whom neither HBcAg nor HBsAg were demonstrable in the liver, suffered exclusively from superinfection of hepatitis B virus carriers and/or coinfection of hepatitis B virus with the delta agent remains to be resolved. Delta infection may occur in isolated settings with no relation to Italian origin, drug addiction, or polytransfusion. The infection is far more widely spread than previously assumed.Six years ago in Italy, Rizzetto and coworkers (1) described the delta agent as a pathogenic factor complicating infection with hepatitis B virus (HBV). It is now thought to contain a small RNA genome surrounded by delta antigen and a coat of HBV surface antigen and to elicit a specific immune response which permits clinical diagnosis of delta infection. The delta agent requires coinfection with HBV for its replication which is associated with inhibition of synthesis of HBV markers. Delta antigen can be demonstrated immunohistochemically in hepatocellular nuclei (2, 3). Delta agent frequently occurs as a superinfection in HBV carriers with preexisting, sometimes minimal, degrees of histologic injury. In these persons, superinfection produces severe deterioration of the clinical and histologic picture often with fatal progression (4,5). Histologically, exacerbation