OBJECTIVE The aim of this study was to compare the potential efficacy and safety of a combination of interferon and ribavirin with that of interferon and amantadine in patients who had previously failed to respond to interferon monotherapy. METHODS A total of 29 patients were randomized to 3 million units of alpha-interferon three times weekly with 1000 mg of ribavirin daily (group A, n = 14) or an identical dose of alpha-interferon and amantadine hydrochloride given in a dose of 200 mg daily (group B, n = 15). Patients were treated for 24 wk and observed for 24 wk posttreatment. RESULTS The treatment groups were evenly matched with respect to gender, frequency of genotype 1, presence of fibrosis, as well as baseline alanine aminotransferase (ALT) and HCV RNA levels. At the end of therapy, five of 14 or 36% of patients in group A versus 0 of 15 in group B had both normal serum ALT and nondetectable HCV RNA by polymerase chain reaction (p = 0.017). A complete response was sustained, however, in only two of 13 patients (15%) in group A who completed 24 wk of observation posttreatment. CONCLUSIONS A substantial proportion of interferon nonresponders have an end-of-treatment biochemical and virological response to a combination of interferon and ribavirin, and sustained responses are possible. The addition of amantadine to interferon, in contrast, does not seem to enhance the antiviral effectiveness of interferon in patients who have previously failed to respond.