OBJECTIVES: To identify factors associated with failure of telaprevir- and boceprevir-based HCV triple therapy at a tertiary referral center in New York. METHODS: Records of 223 patients with genotype 1 HCV mono-infection who initiated triple therapy with peg-IFN/RBV plus telaprevir or boceprevir between 5/2011 and 3/2012 were reviewed. Data were analyzed on an intention-to-treat basis by multivariable logistic regression and classification and regression tree models.  RESULTS: Overall, 172 patients were on telaprevir and 51 were on boceprevir.  Median age was 57 years, 35% were female, 18% were black, 44% had F3-F4 fibrosis (Fib-4 ≥ 3.25), 31% were naïve to treatment, 53% had genotype 1a, and 9% of those tested had IL28B CC genotype. Overall, 48% completed the expected course of therapy. Treatment failure (58% of patients) was associated with insufficient viral suppression or breakthrough (30%), adverse events (14%), relapse (12%), and loss to follow up (2%).  Black race increased the risk of failure (OR: 5.92; 95% CI: 2.34-14.96), whereas HCV genotype 1b (OR:0.36; 95% CI: 0.18-0.69), higher platelets (OR: 0.91 per 10x10/µL; 95% CI: 0.86-0.96), and IL28B CC genotype (OR: 0.28; 95% CI: 0.10-0.84) decreased the risk. In a classification tree, platelets < 137 x 10/µL were the strongest predictor of non-SVR24. The absence of HCV RNA at week 4 (telaprevir) or week 8 (boceprevir) were the only on-treatment variables independently (and inversely) related to non-SVR. CONCLUSIONS: Low platelets were an important negative predictor, suggesting that treatment may be more effective if initiated before the onset of advanced liver disease and thrombocytopenia.(NIDA031095,NIDDK090317,Janssen)