Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.This prospective, multicenter study consisted of 292 patients (median age: 62years) infected with HCV genotype 1. All received 12weeks of TVR in combination with 24weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85g/L.101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135g/L (Hazard ratio [HR], 2.53; p=0.0013), estimated glomerular filtration rate <80ml/min/1.73m2 (HR, 1.83; p=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p=0.0281).Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.