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The IFNL4 ss469415590 polymorphism has recently be shown to better predict treatment response in chronic hepatitis than the IL28B rs12979860 variant. However, no data exist in patients with HIV/hepatitis C virus (HCV) coinfection. Analysing 206 HCV(+)/HIV(+) and 162 HCV(+)/HIV(−) patients, we found that compared with IL28B rs12979860, IFNL4 ss469415590 was strongly associated with response to interferon/ribavirin therapy in HCV(+)/HIV(−) individuals but not in HIV(+)/HCV(+) patients. Thus, effects of the IFNL4 variant may differ in HIV(+) and HIV(−) patients.