To clarify the evolution of antibody to hepatitis C virus (anti-HCV) and of liver histologic findings during the natural course of type-C chronic hepatitis, 111 patients with biopsy-proven chronic hepatitis type C were consecutively enrolled in this study and were followed up biochemically, serologically, and histologically for more than 5 years. All were positive for the first- and second-generation antibody to HCV (anti-HCV-1 and anti-HCV-2). None received antiviral therapy during the follow-up period. At the end of follow-up, all remained positive for anti-HCV-2, but four patients turned negative for anti-HCV-1. HCV RNA, detected by the polymerase chain reaction method, was tested serially in 20 patients who persisted positive anti-HCV-1 and in 4 patients who lost anti-HCV-1. HCV RNA disappeared from only two patients, who lost anti-HCV-1 during the follow-up period. A normalization of the serum transaminase level was found in only two patients, who lost both anti-HCV-1 and HCV RNA. A repeat liver biopsy was performed in 62 patients with chronic hepatitis who were persistently positive for all HCV markers and in 4 patients who lost anti-HCV-1. Of the 62 patients who retained all HCV markers, 16 progressed to hepatocellular carcinoma, 6 to cirrhosis of the liver, and 1 had a normal liver, whereas the remaining 39 had chronic hepatitis. Two patients who lost both anti-HCV-1 and HCV RNA showed a normal liver. Of two patients who lost only anti-HCV-1 one progressed to hepatocellular carcinoma and one to chronic hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)