The anti–hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon‐α2a (PEG IFN‐α2a) were investigated in a multicenter, randomized, double‐blind, placebo‐controlled escalating dose‐ranging phase II study in treatment‐naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN‐α2a 180 μg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 μg/week PEG IFN‐α2a. In patients with genotypes 1 and 4, the 600‐ and 1,000‐mg combination treatments induced a continuous decay in viral load that reached −4.61 ± 1.88 and −4.75 ± 2.19 log₁₀ IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels at week 4 were reduced by −5.91 ± 1.11 and −5.89 ± 0.43 log₁₀ IU/mL, respectively, with the same treatment regimens. Adverse events were comparable between treatment groups apart from a higher incidence of neutropenia associated with PEG IFN‐α2a and an increased incidence of isolated hyperbilirubinemia at the highest dose of Debio 025 (1,000 mg/day). Conclusion: These results confirm that Debio 025 has a potent activity and an additive effect on HCV RNA reduction in genotype 1 and 4 patients at 600 and 1,000 mg/day when combined with PEG IFN‐α2a. (HEPATOLOGY 2009.)