Amantadine, a widely available antiviral drug, has been previously reported to be effective in patients with chronic hepatitis C who failed to respond to interferon-alpha therapy. Nevertheless, its efficacy has not been fully studied, particularly in naive patients. We conducted a pilot study to determine the efficacy and the safety of amantadine as initial therapy in patients with chronic hepatitis C. Fourteen consecutive patients (mean age, 40 years; M/F ratio, 9/5) with chronic hepatitis C, elevated alanine aminotransferase (ALT) and without cirrhosis were treated with a 6-month course of amantadine, 100 mg orally twice daily. Main outcome measures were ALT concentrations and serum hepatitis C virus-RNA (HCV-RNA) levels at the end of therapy. All adverse events were mild or moderate and were not treatment limiting. At the end of treatment, all patients had detectable serum HCV-RNA and only one patient had a normal ALT level. The serum HCV-RNA median level and the ALT median level were not significantly different at the end of treatment as compared to baseline levels. Our results show that amantadine alone cannot be recommended as an alternative therapy in patients with chronic hepatitis C.