BACKGROUND & AIMS: We recently identified a polymorphism upstream ofinterleukin (IL)-28B to be associated with a 2-fold difference insustained virologic response (SVR) rates to pegylated interferon-alfaand ribavirin therapy in a large cohort of treatment-naive, adherentpatients with chronic hepatitis C virus genotype 1 (HCV-1) infection. Wesought to confirm the polymorphism's clinical relevance byintention-to-treat analysis evaluating on-treatment virologic responseand SVR. METHODS: HCV-1 patients were genotyped as CC, CT, or TT at thepolymorphic site, rs12979860. Viral kinetics and rates of rapidvirologic response (RVR, week 4), complete early virologic response(week 12), and SVR were compared by IL-28B type in 3 self-reportedethnic groups: Caucasians (n = 1171), African Americans (n = 300), andHispanics (n = 116). RESULTS: In Caucasians, the CC IL-28B type wasassociated with improved early viral kinetics and greater likelihood ofRVR (28% vs 5% and 5%; P < .0001), complete early virologic response(87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P <.0001) compared with CT and TT. A similar association occurred withinAfrican Americans and Hispanics. In a multivariable regression model, CCIL-28B type was the strongest pretreatment predictor of SVR (odds ratio,5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor ofSVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B typewas associated with a higher rate of SVR (Caucasians, 66% vs 31% and24%; P < .0001). CONCLUSIONS: In treatment-naive HCV-1 patients treatedwith pegylated interferon and ribavirin, a polymorphism upstream ofIL-28B is associated with increased on-treatment and sustained virologicresponse and effectively predicts treatment outcome.