Hepatitis C virus chronic infection is currently the most common cause of end-stage liver disease. The benefit of antiviral therapy on liver histology and its impact on the long-term course of the disease has been extensively studied. However, the results are still equivocal and the overall assessment of treatment effect remains difficult to evaluate. Although the conclusions of the last National Institute of Health Consensus Development Conferences on Hepatitis C have recently been published, several important issues still remain unanswered. We review the available data by an evidence-based approach and conclude that: 1) peginterferon alfa is more effective than conventional interferon in improving liver histology; 2) monotherapy with PEG-interferon induces a marked reduction in staging in virological sustained responders and to a lesser degree in relapsers, but provides no benefit to nonresponders after 24-48 weeks of treatment; 3) maintenance therapy aiming to improve histology in virological nonresponders should be considered experimental and of unproven benefit; 4) although the reduction in the number of events in sustained responders suggests a long-term benefit of IFN therapy, available evidence is still insufficient to confirm that IFN prolongs life in HCV infected patients. Data of the long-term benefit of subjects treated with IFN plus ribavirin are still not available; 5) pooling of published data suggests a slight preventive effect of IFN on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low and the observed benefit might be due to spurious associations. The preventive effect is more evident among sustained responders to interferon.