BACKGROUND Alpha interferon (alpha IFN) treatment normalizes serum ALT levels in at least half of all patients affected by chronic hepatitis C, but a reactivation of the disease is frequently observed after the end of therapy. Different regimens of alpha IFN therapy have been proposed but the optimal schedule is still controversial. Recently at least 6 different types of HCV have been identified and the HCV genotype has been proposed as an important factor influencing the response to alpha IFN therapy. OBJECTIVE The aim of this study was to evaluate the efficacy of different regimens of alpha IFN in chronic hepatitis C, and to study the relationship between the response to treatment and HCV genotypes. METHODS 160 consecutive patients affected by biopsy-proven chronic hepatitis C were randomly treated with different doses of lymphoblastoid alpha IFN [adjusted to the body surface area (m2)] and different durations of therapy, as follows: 2 MU/m2/t.i.w. for 6 or 12 months or 4 MU/m2/t.i.w. for 6 or 12 months. Biochemical and virological responses were studied: ALT levels were monitored monthly during and for at least 6 months after the end of treatment, and serum HCV RNA was assessed before and at the end of therapy, using nested RT-PCR. Biochemical responses were defined in advance as follows: non-response as maintenance of abnormal ALT levels during treatment; complete response as the normalization of ALT by the 4th month and lasting until the end of treatment; sustained response as a complete response lasting for at least 6 months after the end of therapy. The clearance of serum HCV RNA at the end of therapy was considered a virological response. In pre-treatment sera stored at-80 degrees, HCV genotyping was performed according to the method of Okamoto. The Chi square test and multiple stepwise logistic regression were used for the statistical analysis. RESULTS A sustained biochemical response was significantly more frequent in patients treated for 12 than in patients treated for 6 months, independently of the dosage (45% vs 24% in patients treated with 2 MU/m2/tiw, and 55.5% vs 30% in those treated with 4 MU/m2/tiw). The distribution of HCV genotypes (according to the classification of Okamoto) was 9.8% type I, 45.5% type II, 37.1% type III and 7.6% type V. Both the biochemical and virological responses were significantly correlated to the HCV genotype, being significantly more frequent in patients infected with type III or V (71-60% biochemical and 48-50% virological response, respectively) than in patients with type I or II (15% biochemical and 18-21% virological response, respectively). CONCLUSIONS 12 months of alpha IFN treatment seemed to be significantly more efficacious than 6 months of therapy, and a significant relationship between the HCV genotype and the biochemical and virological response to alpha IFN was found.