Standard treatment for chronic hepatitis C currently consists of 3–6 million units (MU) of interferon-α (IFN-α) given thrice weekly (t.i.w.) for 12 months, obtaining rates of sustained response (SR) that usually do not exceed 15–25%. Some recent reports have suggested that daily administration of IFN-α may be more efficacious. More than 7 years ago, when standard therapy for hepatitis C was usually given for 6 months, we conducted a randomized clinical trial comparing daily vs t.i.w. treatment. In this study, 149 patients with chronic hepatitis C were randomized to received 3 MU of IFN-α either t.i.w. for 6 months or daily for 3 months followed by t.i.w. for 3 months. All patients were treated with human leucocyte IFN-α and were followed-up for up to 72 months after inclusion. Overall, patients treated daily or t.i.w. had similar rates of virological response after 3 months of induction [24/49 (50%) vs 40/100 (40%)], at the end of therapy [15/49 (31%) vs 36/100 (36%)] and at the end of follow-up [6/49 (12%) vs 9/100 (9%)]. However, when patients infected with HCV types other than HCV-1 were studied, there was a trend favouring the daily schedule that was associated with a higher [5/20 (25%) vs 5/48 (10%)] rate of long-term SR. All patients with a virological response – hepatitis C virus (HCV) RNA negative in serum as determined using the polymerase chain reaction – at 6 months after therapy remained in biochemical and virological remission at long-term follow-up, while seven of eight subjects who had normal alanine aminotransferase (ALT) levels but were serum positive for HCV RNA at 6 months, relapsed later, indicating that serum HCV RNA is better than ALT at predicting long-term cure after IFN-α therapy in chronic hepatitis C.