Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti–hepatitis C virus activityin vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log10 after a 14-day oral treatment with 1200 mg twice daily (P< 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025–treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 ± 6 (standard error) ng/mg protein (baseline) to 5 ± 1 ng/mg protein at day 15 (P< 0.01).Conclusion:Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti–hepatitis C drugs.