Background: Up to 80% of hepatitis C patients are refractory to treatment with interferon-α. These patients are not likely to benefit from higher dosages or longer duration of interferon alone. The addition of ribavirin has been shown to improve the response rate in patients resistant to a previous course of interferon-α alone. Aim: To evaluate whether a sustained hepatitis C virus (HCV) RNA response could be obtained with combination therapy of interferon-α and ribavirin in patients who did not respond to or relapsed after a standard interferon-α treatment. Methods: A total of 73 patients, 59 non-responders and 14 relapsers after interferon-α alone, were treated with a combination of ribavirin (1000–1200 mg/day) and interferon-α (3 MU three times a week) for 24 weeks. Alanine aminotransferase levels and HCV RNA were checked for 24 weeks after completion of therapy. Results: At the end of the combination therapy, 36 patients (49%) showed alanine aminotransferase normalization and in 20 patients (27%), HCV RNA was undetectable in serum. At the end of the 24 weeks follow-up period, only 12 patients (16%) had a sustained response with serum negativity of HCV RNA. This response was significantly higher in relapsers than in non-responders: five (36%) vs. seven (12%) patients (P=0.03), respectively. Adverse effects were restricted to flu-like symptoms and moderate haemolytic anaemia. Conclusions: Combination of interferon-α and ribavirin is quite limited, both in scope and efficacy, in HCV patients who had a non-response to monotherapy with interferon. Better results may be expected in relapsers, but larger studies are necessary.