ABSTRACT—Aims/Background: Alpha-glutathione S-transferases (α-GST) are the cytoplasmatic class of enzymes responsible for cellular detoxifying processes. We evaluated the plasma α-GST activity in relation to chronic infection caused by hepatitis C virus (HCV). Methods: Eighteen anti-HCV-negative healthy subjects (controls), 32 anti-HCV-positive subjects with a constant normality of alanine aminotransferases (ALT) and gamma-glutamyl transpeptidase (γ-GT) levels (“apparently healthy carriers”), and 85 patients with HCV-related chronic liver disease (40 chronic hepatitis, 27 cirrhosis, and 18 with hepatocellular carcinoma) were studied. We assayed plasma α-GST in all subjects upon their entry into the study; and every 6 months for 3 years in the control group and in anti-HCV apparently healthy carriers. Results: Alpha-GST values were significantly higher than normal values in 57% of the 21 HCV-RNA-positive apparently healthy carriers and in none of 11 persistently HCV-RNA-negative subjects; the highest increment of α-GST was documented in patients with chronic hepatitis. We did not observe correlation among HCV-RNA, histological activity, γ-GT and ALT or α-GST values. Conclusions: Therefore, the increment of plasma α-GST indicates a liver involvement even when ALT levels are normal. This may be clinically relevant to “apparently healthy carriers” whose plasma α-GST values, when increased, might need further evaluation.