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-␣2a (PEG IFN-␣2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naı ¨ve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-␣2a 180 g/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 g/week PEG IFN-␣2a. 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 log 10 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 log 10 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-␣2a 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-␣2a.