Since antibodies to polyalbumin have been noted to occur in patients with hepatitis or cirrhosis, we investigated sera from 219 patients with a variety of acute and chronic liver diseases with and without HBsAg using an ELISA. The prevalence of circulating polyalbumin antibodies was shown to be significantly increased over that of healthy controls (6.7%) in patients with autoimmune chronic active hepatitis (67%), acute viral hepatitis (41%) and fulminant hepatic necrosis (38%), but such antibodies were absent in chronic hepatitis B patients and other liver diseases. Serial studies in acute hepatitis showed evidence of antibodies early in the course of illness with disappearance prior to full recovery. In acute hepatitis B, the presence of polyalbumin antibodies was significantly associated with female sex (p < 0.01), 3-fold higher transaminase levels and shorter duration of clinical illness (<4 weeks in all cases). Polyalbumin antibodies appear to be associated with diseases characterized by active hepatocyte necrosis. Since they are evident early in acute hepatitis B when complexes of polyalbumin and virus are likely, these antibodies may play an adjunctive role to other hepatitis B-related antibodies in the clearance of hepatitis B virus infection.