The discovery of hepatitis C virus (HCV) has enabled the diagnosis of type C chronic liver disease, which had in the past been diagnosed as part of non-A, non-B chronic liver disease. Although most cases with chronic liver disease are caused by hepatitis B virus (HBV) or HCV infection, there are still cases of non-B, non-C chronic liver disease. Forty patients with chronic liver disease, who were seronegative for hepatitis B surface antigen and antibody to HCV, were followed for a mean period of 72 months. The clinical manifestations in these patients were compared with those reported for type B and type C chronic liver disease. Of the 40 patients, 22 were diagnosed with chronic hepatitis, 14 with liver cirrhosis and 4 with hepatocellular carcinoma (HCC). Twenty-seven (67.5%) patients showed mild alanine aminotransferase activity profiles, and the natural clinical course of most patients showed a slow progression compared with that reported for type B and type C patients. The yearly incidence of HCC was 9.7% in patients with liver cirrhosis and 3.9% in chronic hepatitis. These rates were similar to those in type B or type C patients. This suggests that our population sample contained a number of patients with type B, type C or other etiologic agent(s), because 66.7% of the patients who developed HCC had some evidence of exposure to HBV or HCV. Our results suggest that more detailed and accurate tests for detecting HBV and HCV should be considered before making the diagnosis of non-B, non-C chronic liver disease, and that there is the need to reveal unknown etiologic agent(s).