INTRODUCTION: Chronic hepatitis C virus infection (HCV) is the most common infectious disease among intravenous drug users. AIMS: To determine and compare compliance rates between two groups of chronic HCV patients from the methadone substitution program of the National Greek Organization Against Drugs treated with either pegylated interferon alpha-2b/ribavirin or with interferon alpha-2b/ribavirin during 48 weeks of therapy and 24 weeks of follow-up. Furthermore, to evaluate the efficacy of each treatment modality. METHODS: Forty-five consecutive methadone maintenance (MM) patients (group A, 36 males, nine females) were treated with pegylated interferon alpha-2b (weight-based dosing 1.5 microg/kg/week) and ribavirin 1000-1200 mg/day orally. Sixty-five consecutive MM patients (group B, 52 males, 13 females) were treated with interferon alpha-2b (6 MIU, three times/week) and ribavirin with the doses reported above. During the study, all patients were followed up periodically by hepatologists, internists, and psychiatrists. RESULTS: Baseline characteristics were similar between the two groups. Thirty-four out of 45 patients (75.6%) from group A and 31 of 65 patients (47.7%) from group B completed therapy (P =0.006). Thirty-two (71.1%) patients from group A and 27 patients (41.5%) from group B were followed-up until the end of week 72 (P = 0.004). At the end of the follow-up, sustained virologic response was achieved in 23 of 45 (51.1%) patients from group A and 21 of 65 patients (32.3%) from group B (P =0.075). CONCLUSION: Pegylated interferon alpha-2b/ribavirin treatment achieved a significantly higher compliance rate than interferon alpha-2b/ribavirin in MM patients with chronic HCV infection. After 24 weeks of follow-up, response rates were similar for patients who were compliant to treatment for both groups.