Background & Aims: Some patients with serum hepati- tis C virus (HCV) have persistently normal aminotrans- ferase (ALT) levels and are affected by cirrhosis. This study prospectively evaluated progression of the dis- ease in a group of anti-HCV–positive patients with persistently normal ALT levels. Methods: Thirty-seven subjects were studied. Each subject underwent liver biopsy at baseline and after 5 years of follow-up. At baseline, serum samples were tested for genotypes and HCV RNA load. ALT levels and serum HCV RNA were tested every other month and every 6 months, respec- tively. Patients with increased ALT were discharged from the study and treated with IFN. Five years after the end of IFN therapy, a liver biopsy was performed. Results: Liver biopsy at baseline showed chronic hepa- titis in 34 patients and normal histology in 3 patients, 2 of whom were negative for HCV RNA and 1 positive. HCV genotypes were distributed as follows: 2a, 56%; 1b, 41%; and 1a, 3%. At the end of 7-year follow-up, 73% of the patients still had normal ALT values. Liver histology after 5 years was comparable to that ob- served at entry to study. Conclusions: Most patients with persistently normal ALT serum levels have very mild chronic hepatitis. However, healthy anti-HCV– positive subjects exist. In patients with HCV-related chronic hepatitis associated with persistently normal ALT levels, the grade of disease activity does not increase over years and progression to cirrhosis is slow or absent.