Autoantibodies to the human asialoglycoprotein receptor (anti-h-ASGPR) were studied with a solid-phase ELISA in the sera of 421 patients with inflammatory liver diseases, 288 patients with various other disorders and 31 controls. Anti-h-ASGPR were found predominantly in autoimmune chronic active hepatitis (44 of 88, 50%) and were closely related to inflammatory activity. In a subpopulation of these patients with untreated, biopsy-proven active disease or relapse, 15 of 17 were positive (88%). In contrast, only 11 of 204 patients (5.3%) with viral hepatitis were anti-h-ASGPR receptors-positive (chi 2 analysis; p less than 0.001). We also compared the occurrence of anti-h-ASGPR with antibodies to rabbit and rat asialoglycoprotein receptors in 352 sera. In contrast to the anti-human asialoglycoprotein receptor antibodies (3 of 107), anti-rabbit- or anti-rat-asialoglycoprotein receptor antibodies were found in 21 and 28 of 107 cases of viral hepatitis, indicating that different epitopes were recognized by these sera. In various other diseases anti-human asialoglycoprotein receptor antibodies were rarely found. Some sera from patients with connective-tissue diseases (8 of 73) and primary or secondary liver malignancies (6 of 55) exhibited anti-h-ASGPR. In autoimmune chronic active hepatitis the presence of anti-human asialoglycoprotein receptors did not correlate to other established autoantibody systems. Thus we conclude that anti-human asialoglycoprotein receptor antibodies can serve as diagnostic markers for inflammatory active cases of autoimmune chronic active hepatitis. Immune reactions to the asialoglycoprotein receptor, which is expressed on the hepatocellular membrane as a liver-specific antigen, might contribute to the pathogenesis of autoimmune chronic active hepatitis.