Although the antiviral effects of amantadine sulphate (1-aminoadamantan sulphate) have not been characterized for the hepatitis C virus (HCV), previous pilot studies have suggested promising results in patients with chronic hepatitis C. The aim of the present study was to compare the efficacy, safety, and health-related quality of life (HRQOL) of interferon alfa (IFN-α) alone or in combination with oral amantadine for treatment of chronic hepatitis C. One hundred nineteen previously untreated patients with chronic hepatitis C were randomly allocated to treatment with IFN-α2a at a dose of 6 megaunits 3 times a week subcutaneously for 24 weeks, followed by 3 megaunits thrice weekly for an additional 24 weeks plus amantadine sulphate administered orally 100 mg twice a day for 48 weeks or the same IFN regimen plus a matched placebo. The primary endpoint was undectable serum HCV RNA (<1,000 copies/mL) at week 24 after treatment. At the end of treatment and the 24-week follow-up period serum HCV RNA was undetectable in 20 (34%) and 6 (10%) of the 59 patients treated with the combination IFN-α plus amantadine and in 20 (33%) and 13 (22%) of the 60 patients treated with IFN-α alone, respectively (P = n.s.). Discontinuation of therapy for adverse events was similar in both treatment groups. Although treatment with IFN-α worsened HRQOL, combination with amantadine showed a substantial trend to improve fatigue and vigor. In conclusion, combination therapy IFN-α plus amantadine is as effective as IFN-α monotherapy in previously untreated patients with chronic hepatitis C.