This case-control study evaluated the real need for liver biopsy in subjects with persistently normal aminotransferase values over a long period by comparing the histological features of these subjects with those of patients with abnormal aminotransferase values. We considered as "Cases" all 32 consecutive anti-HCV/HCV-RNA positive subjects with at least eight normal serum ALT values during the last twelve months; for each "Case", we selected as a "Control" one anti-HCV/HCV-RNA positive patient with at least two abnormal serum ALT values during the last twelve months. The Cases and Controls were matched for age ( 5 years) and sex. In the Case group, 1 subject showed normal liver tissue, 18 minimal chronic hepatitis (CH) and 13 mild CH. In the Control group, 7 subjects showed minimal CH, 19 mild CH, 3 moderate CH, 1 severe CH and 2 cirrhosis. The subjects in the Control group showed a significantly higher HAI score (5.39+2.81) than those in the Case group (2.96+1.62, p < 0.001). The subjects in the Control group more frequently showed a fibrosis score greater than 1 (28.1%) compared to the Case group (9.4%; p<0.05). Finally, steatosis was more frequent and more severe in the Control group than in the Case group (respectively, 78.1% vs 50%, p < 0.05; and 1.47+1.16 vs 0.6+0.71, p < 0.001). The HAI and fibrosis scores did not correlate with the ALT value, HCV genotype or HCV viral load in either the Case or Control group. Our findings showed that the subjects with a persistently normal serum ALT value had minimal or mild chronic hepatitis, thus demonstrating that a liver biopsy is not indicated for these subjects.