Background & Aims The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. Methods Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. Results In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. Conclusions In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.