Background/Aims : The antiviral agent amantadine may have activity against the hepatitis C virus. To determine whether the combination of interferon-alpha plus amantadine was more effective than interferon monotherapy we conducted a multicentre clinical trial in untreated patients with chronic hepatitis C infection. Methods : We performed a pilot study in two centres (36 patients) to determine the number needed for a statistically significant clinical trial and then conducted a multicentre, randomized controlled clinical trial involving 14 centres and 143 patients. Results : There was no significant difference in sustained response rates in patients receiving interferon and amantadine compared to those receiving interferon alone. The on treatment response rate at 3 months was 65% on combination vs. 49% on interferon alone ( P =0.05) while the sustained response was 18 and 15%, respectively. Conclusions : Combination therapy with interferon plus amantadine does not lead to a significant increase in sustained response rates when compared to interferon monotherapy.