In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting. We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012. Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02). In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.