Antibodies directed against glutaraldehyde-polymerized human serum albumin (pHSA) were tested by a sensitive and specific enzyme-linked immunosorbent assay (ELISA) in serum samples from 196 patients with various hepatic and non-hepatic diseases and in 38 healthy control subjects. A very high prevalence (80.1%) of antibody response was found in the patient group, ranging from 60% in type non-A, non-B (NANB) chronic active hepatitis (CAH) and lymphomas to 95.5% in hemodialysis patients. A higher prevalence of anti-pHSA antibodies was found in hepatitis B virus (HBV)-related CAH and hemodialysis patients compared with NANB-related CAH, collagen diseases and lymphomas. Anti-pHSA antibodies were most frequent in HBsAg-positive cases, but no correlation between antibody response and the HBeAg/anti-HBe status was found among these patients. Anti-pHSA antibodies did not correlate with HBsAg-associated pHSA receptors determined by radioimmunoassay (RIA). Moreover, a significantly higher pHSA receptor expression was found in HBV-related CAH and hemodialysis patients compared with chronic HBsAg carriers and in HBeAg-positive patients compared with HBeAg-negative cases. The anti-pHSA response seems to be related to the presence of immunoregulation disorders which may be induced by several causes, such as autoimmunity and viral infections. In particular, as far as the HBV infection is concerned, there is no evidence that circulating anti-pHSA antibodies interfere with the natural course of the disease.