We studied 333 chronic hepatitis C patients to evaluate the natural course of this disease. Among 57 patients undergoing serial biopsies, 20 had chronic persistent hepatitis (CPH) at the first biopsy, and 10 of them progressed to chronic active hepatitis (CAH) or liver cirrhosis (LC) after 11 yr. Sixteen patients had CAH 2A, and this progressed to CAH 2B or LC in 10 cases over 9 yr. Among the 21 patients with CAH 2B, progression to LC was noted in 15 after 7 yr. Among the 100 patients observed for over 5 yr, the normalization of liver function for at least 3 yr was seen in only four patients. In two of these four patients, serum HCV-RNA was tested serially. Despite the sustained normalization of alanine aminotransferase levels, HCV-RNA continued to be detectable in one patient. We conclude that many patients with chronic hepatitis C eventually show progression of their disease after a long and symptomless course.