Background: Alpha interferon (IFN) alone or in combination with Ribavirin (RBV) is the treatment of choice for HCV related chronic liver disease. There are many types of alpha IFN and to date only few reports are available comparing different types of alpha interferon. We run a randomised controlled trial with the aim to compare tolerability and efficacy of two different types of IFN: recombinant alpha 2b interferon (IFN-R) and leukocyte alpha n-3 interferon (IFN-L) at the same dosage of 3 MU subcutaneously thrice weekly for one year. Methods: one hundred sixty eight consecutive anti-HCV positive naive patients, 34 mild chronic active hepatitis (MCH), 81 moderate-severe hepatitis (MSCR) and 53 active cirrhosis (CIRR) that met the inclusion criteria were enrolled into the study. The diagnosis of HCV chronic liver disease was established by liver biopsy performed on patients with abnormal serum alanine aminotransferase (ALT) value for at least one year. HCV serology: all patients were tested for confirmatory test RIBA II, HCV-RNA, and identification of viral genotype. Patients were randomised to receive either IFN-R or IFN-L. Follow-up continued for at least two years after stopping treatment. Results: no significant differences were observed between the two groups of treatment as far as the incidence of side effects is concerned. Tolerability was good: only 11 in IFN-R and 8 patients IFN-L group respectively had to stop therapy due to side effects. The two types of IFN showed a comparable efficacy: an end of therapy response was observed in 34% of IFN-R and 30% of IFN-L patients; a sustained response was seen in 16% of IFN-R and in 19% of IFN-L patients. Conclusion: in the treatment of patients with chronic hepatitis C there was no statistically significant difference in tolerability and efficacy between the two IFNs tested.