In patients with chronic active hepatitis (CAH), the absence of the conventional serum auto-antibodies (antinuclear, smooth muscle and liver-kidney microsomal) is often taken as evidence against an auto-immune aetiology and as indicative that the disease is unlikely to respond to immunosuppressive therapy. We report 12 British patients (11 female) who presented with histologically florid CAH (11 with cirrhosis or fibrosis and seven with ascites) but without significant titres of these antibodies or any other demonstrable aetiological feature (cryptogenic CAH), who have been followed up for a median of 5.25 years (range: 0.75-16 years). Ten had hypergammaglobulinaemia and/or specific elevations of serum IgG concentrations at presentation and five of 10 patients tested were found to have the HLA allotypes B8 and DR3. Remission was initially induced with prednisolone with or without azathioprine in all patients. Six patients subsequently relapsed on one or more occasions, either spontaneously while on maintenance therapy or during attempts to withdraw corticosteroids, and required increases or reintroduction of immunosuppressive therapy to regain disease control. Retrospective analysis of pretreatment samples from 11 of the patients revealed that all had been seropositive at presentation for auto-antibodies against the liver membrane lipoprotein preparation known as liver-specific membrane lipoprotein (LSP) and/or against the hepatic asialoglycoprotein receptor (ASGP-R), titres of which subsequently fluctuated in direct relation to response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)