Background & Aims A substantial proportion of hepatitis C virus genotype 1 (HCV-1) patients achieved a sustained virological response (SVR, HCV RNA seronegative throughout 24 weeks of post-treatment follow-up) after 24 weeks peginterferon/ribavirin therapy. We explored the role of interleukin-28B genotype in identifying patients who responded to the regimen. Methods Interleukin-28B rs8099917 genotype was determined in 226 HCV-1 patients with 24 weeks peginterferon/ribavirin. Results Compared to patients with rs8099917 TG/GG genotype, those with TT genotype had significantly higher rapid virological response (RVR, HCV RNA seronegative at treatment week 4, 54.0% vs. 17.9%, p <0.001) and SVR (64.7% vs . 25.6%, p <0.001) rates, and lower relapse rate (28.0% vs . 54.5%, p = 0.01). Logistic regression analysis revealed that the strongest factor predictive of a RVR was the carriage of rs8099917 TT genotype (odds ratio/ 95% confidence intervals OR/CI: 6.24/2.34–16.63), followed by lower viral loads (OR/CI: 5.29/2.81–9.93) and age (OR/CI:0.94/0.91–9.97). The most important factor predictive of an SVR was the attainment of a RVR (OR/CI: 22.23/9.22–53.58), followed by the carriage of rs8099917 TT genotype (OR/CI: 3.38/1.18–9.65), lower viral loads (OR/CI: 2.23/1.00–4.93) and ribavirin exposure dose (OR/CI: 1.17/1.06–1.30). The determinant power of rs8099917 genotype on SVR was mainly restricted to non-RVR patients, particularly those with higher baseline viral loads. Combination of the two pretreatment predictors, interleukin-28B genotype and baseline viral loads, could predict treatment efficacy with a positive predictive value of 80% and a negative predictive value of 91%. Conclusions Interleukin-28B genotype could help identifying patients who are or are not candidates for an abbreviated regimen before treatment.