Alisporivir is a cyclophilin inhibitor with demonstrated in vitro and in vivo activity against hepatitis C 11 virus (HCV). We estimated antiviral effectiveness of alisporivir alone or in combination with 12 pegylated-Inteferon (peg-IFN) in 88 patients infected with different HCV genotypes treated for four 13 weeks. The pharmacokinetics of both drugs were modeled and used as driving functions for the viral 14 kinetic model. Genotype was found to significantly affect pegylated-Inteferon effectiveness (ε= 86.3% 15 and 99.1% in genotype-1/4 and genotype-2/3, respectively, p<10 -7) and infected cells loss rate (δ= 16 0.22 vs 0.39 day -1 in genotype-1/4 and genotype-2/3, respectively, p<10 -6). Alisporivir effectiveness 17 was not significantly different across genotype and was high for doses ≥600 mg QD. We simulated 18 virologic responses with other alisporivir dosing regimens in HCV genotype-2/3 patients using the 19 model. Our predictions consistently matched the observed responses, demonstrating that this model 20 could be a useful tool for anticipating virologic response and optimize alisporivir-based therapies.