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Retreatment of interferonresistant chronic hepatitis C represents a significant clinical challenge. In an openlabel, pilot study, the safety and efficacy of interferon alpha2b, ribavirin, and amantadine were assessed. Twenty patients with chronic hepatitis C who had previously failed to respond to a course of interferon monotherapy followed by a course of combination therapy 10 patients received interferon alpha2b 3 million units three times a week plus ribavirin 800 mgd and 10 patients received interferon alpha2b 3 million units three times a week plus amantadine 200 mgd were enrolled in this retreatment protocol. One month after discontinuation of their last regimen, patients started treatment with interferon alpha2b 3 million units three times a week, ribavirin 1,000–1,200 mgd, and amantadine 200 mgd. Biochemical and virologic end points were monitored. Patients with hepatitis C virus HCV RNA levels of <100 copiesmL at the end of 24 weeks of therapy completed a 48week course of interferon alpha2b, ribavirin, and amantadine treatment. Of the enrolled subjects, 60 were male, 85 were white, 85 had HCV genotype 1, and 20 had histologic cirrhosis. The mean age ± SD of the patients was 44.1 ± 4.9 years, the mean baseline HCV RNA level ± SD was 1,845,150 ± 1,279,069 copiesmL, and the mean baseline alanine aminotransferase level ± SD was 130 ± 100 UL. Five patients 25 became HCV RNA negative <100 copiesmL after 24 weeks of treatment, with only three patients 15 remaining HCV RNA negative at the end of 48 weeks of treatment. This end of treatment response was sustained 6 months after the discontinuation of treatment in only two patients 10. In this interferonresistant group, a treatment regimen of interferon alpha2b, ribavirin, and amantadine was associated with only a 10 sustained viral eradication rate.