Summary. Acute hepatitis C virus (HCV) infection evolves to chronicity in 50–84% cases. Treatment with interferon-α (IFN-α) was repeatedly found to provide sustained cure rates higher than that in chronic HCV infection, but the optimal treatment strategy has not yet been defined. In a multicentre open-label study, we investigated the therapeutic performance of a short course of pegylated (peg) IFN-α in patients with acute HCV hepatitis. Peg IFN-α2b, 1.0–1.5 μg/kg weekly, was administered for 12 weeks. Forty-six patients were enrolled; 26 of them were intravenous drug users. Eleven patients had jaundice. Treatment was started within 1–90 days from the peak alanine aminotransferase. Treatment was well tolerated with a single dropout (2%). Thirty-three of 46 patients (72%) had a sustained virological response (SVR) after a 6 months post-treatment follow-up, 8 (17%) relapsed after treatment and 4 were nonresponders (9%). A lower peak viraemia, receiving at least 1.2 μg/kg of peg IFN-α, and a negative HCV-RNA at week 4 and week 12 were predictors of SVR. Thus, in patients with early (week 4) viral response, a short course of peg IFN-α at a weekly dose >1.2 μg/kg, may be a valuable option for the treatment of acute HCV hepatitis.