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Injection drug users are often excluded from hepatitis C virus (HCV) treatment. This study compares sustained virological response, adherence, and quality of life in patients with or without a history of illicit drug use in routine clinical practice.This is a post-hoc analysis of a prospective, observational study conducted in 1860 patients who received peginterferon α-2b/ribavirin combination therapy. Nondrug users (NDUs) were defined as patients without a history of drug addiction; former drug users (FDUs) as patients who had stopped using illicit drugs or opioid maintenance therapy and active drug users (ADUs) as patients using illicit drugs or on opioid maintenance therapy. Virological response, adherence, and the health-related quality of life were assessed by the measure of HCV RNA in the serum, self-report and 36-item short-form health survey Questionnaire, respectively.The analyzed population included 1038 (56%) NDUs, 578 (31%) FDUs, and 244 (13%) ADUs. About 85% of ADUs were on opioid maintenance therapy and 25% used illicit drugs. Although ADUs had a more chaotic lifestyle and more psychiatric disorders, sustained virological response of ADUs (58%) did not differ from that of NDUs (49%) and FDUs (51%) (P=0.133). Adherence rates were 39% in NDUs and FDUs, and 37% in ADUs (P=0.883). Health-related quality of life was improved in the three groups after the end of treatment.Our study suggests that HCV therapy in ADUs on opioid maintenance therapy is as effective as in other HCV patients. The effectiveness of HCV therapy in illicit drug users needs to be evaluated in further studies.