The significance of repeatedly normal serum aminotransferase activities in antihepatitis C virus (anti-HCV)-positive patients is not clear. To address this issue, the authors analyzed clinical, virologic, histopathologic, and biological characteristics of such subjects. Among their active file of 1,200 anti-HCV-positive immunocompetent patients, they identified 36 subjects (3%) with repeatedly normal aminotransferase activities, as defined by at least four normal values of aminotransferase over a minimum period of 6 months without any abnormal value (mean of this period, 31 +/- 21 months). The 36 patients included 11 men and 25 women with a mean age of 45 +/- 15 years. Twenty-three of these 36 subjects (64%) had detectable HCV viremia by polymerase chain reaction. Their genotype distribution was as follows: genotype 1a or 1b, 57%; genotype 2, 26%; and genotype 3, 17%. Of the HCV ribonucleic acid (RNA)-positive and HCV RNA-negative subjects, 17 and 5 had a liver biopsy respectively. In the former, the mean Knodell score was 5.6 +/- 3.5 (range, 1 to 14), and was < 5 in 9 patients (53%) and > or = 5 in 8 (47%), including extensive fibrosis (n = 2) or cirrhosis (n = 2). In the HCV RNA-negative subjects, one patient had a Knodell score > or = 5. Comparing the 23 immunocompetent viremic subjects with repeatedly normal serum aminotransferase activities with our group (n = 564) of immunocompetent viremic patients with abnormal aminotransferase activities, there was a significant predominance of women (70% versus 44%, p < 0.05) and of genotype 2 in the former (26% versus 7%, p < 0.05), but no differences according to quantitative viremia, alcohol consumption, or distribution of risk factor were observed. Most of viremic HCV-infected patients with long-term and repeatedly normal aminotransferase values have indeed chronic active hepatitis, including extensive fibrosis or cirrhosis in as many as 20% of patients. This emphasizes the need for serum HCV RNA determination in anti-HCV-positive patients with normal aminotransferase activities. In these patients liver biopsy may be necessary and should be discussed.