The purpose of this study was to evaluate if a retreatment with natural human interferon alpha could lead to a recovery of the therapeutic responsiveness in non-responder patients with chronic hepatitis C who did (9 cases) or did not (14 cases) develop anti-interferon neutralizing antibodies while on treatment with recombinant interferon alpha2a. During retreatment, no patient developed detectable levels of neutralizing antibodies to natural interferon. At the end of retreatment, 6/9 positive patients showed a complete response to natural interferon therapy, while only 1/14 negative patients had a partial response. These data suggest that a second course of treatment with the natural preparation may be useful in patients who failed to respond to an earlier course of recombinant interferon, particularly the anti-interferon positive patients who showed hepatitis reactivation after an initial response concomitantly with antibody appearance. Conversely, a second course of natural interferon therapy might be useless in cases in which the lack of response is not associated to antibody development.