<i>Objective:</i> We report elevated serum alanine aminotransferase (ALT) levels during pegylated interferon (PEG-IFN)-α-2a in a patient with chronic HCV without other clinical manifestations. <i>Case Summary:</i> A 38-year-old man presented for HCV infection evaluation. Serum aspartate aminotransferase (AST) and ALT levels were 43 and 116 U/l, respectively; RT-PCR blood analysis revealed HCV-RNA infection. PEG-IFN-α-2b plus ribavirin treatment induced both a rapid virologic response and a normalization of transaminase plasma levels. During follow-up, an increase in transaminase and HCV-RNA values prompted us to start a new antiviral treatment with PEG-IFN-α-2a plus ribavirin. Four months later, after the follow-up, a new blood test documented both a HCV-RNA titer <50 U/ml and an increase in ALT and AST plasma levels. Immunostaining of the liver biopsy showed an accumulation of PEG-IFN-α-2a. PEG-IFN-α-2a elimination and the addition of recombinant IFN-α-2a induced normalization of the plasma transaminase levels in about 2 months. <i>Conclusion:</i> We postulate PEG-IFN-α-2a treatment because both the molecular weight and the distribution volume of the PEG-IFN may accumulate in the liver resulting in an increase of plasma transaminase levels. In contrast, during PEG-IFN-α-2b treatment, we did not document any increase in plasma transaminase values probably because of the lower molecular weight of the PEG.