Standard therapies for the treatment of hepatitis C are ineffective in almost 50% of patients. Amantadine is an antiviral agent that may have activity against hepatitis C virus. In this pilot study, we evaluated the efficacy of a combination of interferon, ribavirin, and amantadine in patients with chronic hepatitis C who had previously failed 6–12 months of treatment with interferon and ribavirin. In this prospective open-label study, 23 patients were treated with a combination of interferon-α2b 3 million units subcutaneously three times per week, ribavirin 1000–1200 mg daily, and amantadine 100 mg twice daily for 6–12 months. Treatment was discontinued at 6 months if the patients had detectable HCV RNA by PCR. All patients were followed for 6 months after the completion of treatment. At the end of treatment, the biochemical response was 47% and the virological response was 30%. However, the rate of sustained virological response was only 13% (3/23). There were no unexpected side effects with triple therapy. In conclusion, triple therapy with interferon, ribavirin and amantadine resulted in a low sustained viral clearance in chronic hepatitis C patients who had previously failed interferon and ribavirin combination therapy.