METHODS This study prospectively evaluated the progression of liver disease in a group of anti-HCV-positive patients with persistently normal ALT levels (PNALT) who were HCV-RNA positive. Patients selected for this study were those who presented with PNALT according to the Italian Association for the Study of the Liver (AISF) criteria in the year 1995/96 and underwent liver biopsy. They were divided into two groups according to their ALT evolution. Forty-five patients were included in this study. RESULTS After a median follow-up time of 180 months twenty-five of them maintained PNALT, but two of these developed liver cirrhosis (LC) in a mean time of 174 and 202 months, respectively. Twenty patients had flares of ALT and three of them developed LC in a mean time of 162-178 months. Twelve of these patients underwent current antiviral treatment; six patients were SVR. At baseline, the 5 patients who progressed to LC had age and BMI significantly higher than patients without LC (P < 0.005 and P < 0.01, respectively). Grading (P < 0.006) and staging (P < 0.003) were also more severe at histology, while serum HDL-C levels were statistically lower (P < 0.002). Comparing patients with flares of transaminases with and without LC, we found a significant difference at baseline for age, BMI, HDL-C, grading and staging (P < 0.05; P < 0.01 and P < 0.003, respectively). CONCLUSIONS In HCV-RNA positive patients associated with PNALT the grade of disease activity increased over the years in only half of patients and a higher degree of liver fibrosis at baseline was the major relevant factor for progression.