The aim of this work was to assess the effect of a high-dose (10 million units, MU) short-duration (14 weeks) interferon-alpha2b (IFN-alpha2b) regimen in relapsers compared with the standard IFN regimen of 3 MU three times weekly (t.i.w.) for 6 months. Fifty-eight non-cirrhotic patients (who had relapsed after previous treatment with IFN) with chronic hepatitis were randomized: 29 to the high-dose, short-duration regimen and 29 to the standard regimen. By the end of IFN therapy, in the high-dose, short-duration group alanine aminotransferase (ALT) normalization was observed in 23 (79%) of 29 patients, and undetectable hepatitis C virus (HCV) RNA in eight (28%) vs 25 (86%) and 11 (38%) of the 29 patients in the standard group, respectively (P = NS). At the end of the 72-week follow-up, in the high-dose, short-duration group a sustained ALT normalization was observed in two (7%) patients, and undetectable HCV RNA in 0 (0%) vs five (17%) and four (14%) patients in the standard group (P = NS). There was less fibrosis improvement in the high-dose, short-duration group (two of 26 patients, 8%) than in the standard group (eight of 25 patients, 32%) (P = 0.04). Tolerance to IFN was good and similar in the two groups. In conclusion, in IFN relapsers, high-dose, short-duration treatment with IFN-alpha has no advantage when compared to a 6-month treatment with 3 MU IFN t.i.w.