Alisporivir (ALV) is a first in class cyclophilin inhibitor in clinical development with potent activity against hepatitis C virus (HCV) [1]. Here we aimed to estimate the antiviral effectiveness of combination treatment with ALV and pegylated Inteferon (Peg-IFN) in patients infected with different HCV genotypes (GT 1, 2, 3, 4). For that purpose we analyzed the pharmacokinetics (PK) of both drugs and the viral kinetics (VK) observed in 88 patients treated for four weeks with different doses of ALV (200, 600 or 1000 mg) +/- weekly injections of Peg-IFN (Study DEBIO-025-A2203). The PK of ALV was best described by a two compartment model with Michaelis-Menten elimination and time-dependent bioavailability. Further we found a significant effect of Peg-IFN on the clearance of ALV. PK model predictions of ALV and Peg-IFN were used as a driving function for the viral kinetic model [2]. A model assuming multiplicative effect of both agents (ALV and Peg-IFN) in blocking viral production could describe well the viral load data and allow teasing out the effects of ALV and Peg-IFN. GT was found to significantly affect Peg-IFN effectiveness, ε^IFN (median ε= 86.3% and 99.1% in HCV GT-1/4 and GT-2/3, respectively, p=10^-7) and the infected cells’ loss rate, d (mean d = 0.22 vs 0.39 day^-1 in GT-1/4 and GT-2/3, respectively, p=10^-6). ALV’s effectiveness, ε^ALV, was not significantly different across GT and was higher at doses ≥ 600 mg QD (median ε^ALV= 50.5%, 89.4%, 97.1% and 93.6% in 200, 600 and 1000 mg  dual therapy and 1000 mg monotherapy, respectively). The model was used to simulate various ALV dosing regimens without IFN in HCV GT-2/3 patients and could well predict the virological responses observed, suggesting this model may be a useful predictive tool for ALV use with and without IFN and optimal duration of ALV treatment.