BACKGROUND To evaluate the efficacy of the monotherapy with recombinant 2a, 2b and lymphoblastoid alpha Interferon in Chronic Hepatitis C. PATIENTS AND METHODS. Fifty-nine naïve patients, ranging in age from 22 to 65 years, were studied. All had high level of ALT and detectable persistent HCV-viremia; in all patients viral genotype was defined; a liver biopsy was done in the last 24 months; none patient had absolute contraindications to Interferon. The patients received recombinant 2a, 2b or lymphoblastoid alpha Interferon at the dose of 5 (or 6) million units thrice weekly for six months; then, at the dose of 3 million units thrice weekly for further six months; in patients with low probability of response the initial dose was continued for all cycle. RESULTS Two patients (3.3%) had severe intolerance during the first two months of treatment, therefore the therapy was stopped; 18 patients (30.5%) showed absence of biochemical and/or virological response (no-responders); among thirty-nine patients who presented end of treatment response (ETR), 23 patients (38.9%) relapsed in the six months follow-up (Relapsers), 16 patients (27.1%) showed sustained response (sustained responders). No evidence of break-through, no evidence of late relapses were observed. None patient infected with genotype 1b had sustained response. CONCLUSIONS Although the cohort studied was small, a rate of sustained response, like the most common published case reports, was observed. The low sensibility of the genotype 1b at motherapy with interferon is emphasized. Stress is laid on the importance of alternative strategies in the therapeutical management of chronic hepatitis C.