To investigate the possible involvement of autoimmune reactions in the periportal hepatocellular damage that is often seen in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), sera from 35 patients with PBC and 31 with PSC were tested for autoantibodies against the liver-specific lipoprotein preparation, LSP, and against one of its liver-specific constituents, the asialoglycoprotein receptor (ASGP-R), and compared with results in 24 untreated patients with autoimmune chronic active hepatitis (AI-CAH). Anti-LSP antibodies were found in 48.5% of the PBC and 10% of the PSC patients, vs. 100% of those with AI-CAH, while anti-ASGP-R was found in 23% of PBC, 10% of PSC and 96% of AI-CAH patients. In PBC (but not in PSC) these antibodies correlated with severity of periportal inflammation and piecemeal necrosis but tended to be associated with the later stages of the diseases and both seropositivity for, and titres of, anti-LSP and anti-ASGP-R were significantly influenced by the presence of HLA DR3 (positively) and DR2 (negatively) in these patients. DR3 was also associated with significantly higher, and DR2 with lower, serum IgG concentrations in PBC. The findings suggest that, in PBC, DR2 and DR3 may be associated, respectively, with one or more genes that code for down-regulation or for elevation of overall immunoresponsiveness and that autoreactivity to hepatocellular antigens in PBC is more likely to be a consequence than a cause of hepatocellular injury. Periportal liver damage in PSC seems to involve different mechanisms.