Background & Aims: SCH 503034 is a novel and potent oral hepatitis C virus (HCV) protease inhibitor. In this phase Ib study, we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated (PEG) interferon (IFN) α-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-α-2b ± ribavirin therapy. Methods: This was a multicenter, open-label, 2-dose level, 3-way crossover, randomized (to crossover sequence) study carried out in 3 medical centers in Europe. Adult patients received SCH 503034 200 mg (n = 14) or 400 mg (n = 12) 3 times daily orally and PEG-IFN-α-2b 1.5 μg/kg subcutaneously once each week. Patients received SCH 503034 as monotherapy for 1 week, PEG-IFN-α-2b as monotherapy for 2 weeks, and combination therapy for 2 weeks with washout periods between each treatment period. Results: Combination therapy with SCH 503034 and PEG-IFN-α-2b was well tolerated, with no clinically significant changes in safety parameters. Mean maximum log10 changes in HCV RNA were −2.45 ± 0.22 and −2.88 ± 0.22 for PEG-IFN-α-2b plus 200 mg and 400 mg SCH 503034, respectively, compared with −1.08 ± 0.22 and −1.61 ± 0.21 for SCH 503034 200 mg and 400 mg, respectively, and −1.08 ± 0.22 and −1.26 ± 0.20 for PEG-IFN-α-2b alone in the 200 mg and 400 mg SCH 503034 groups, respectively. Conclusions: SCH 503034 plus PEG-IFN-α-2b was well tolerated in patients with HCV genotype 1 nonresponders to PEG-IFN-α-2b ± ribavirin. These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat, nonresponder patient population.