AIM: To build a population pharmacokinetic (PopPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. METHODS: Prospective, open-label, single-center clinical trial(EudraCT:2011-002900-34;CINEBENZclinicaltrials.govnumber:NCT01755403), approved by the local ethics committee. Patients received 2.5mg/kg/12h (Abarax(R), Elea Laboratory, Argentina) for 60 days. Plasma BZN samples were taken at several times along the study and analyzed by HPLC-UV. The PopPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion and residual variability were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate the BNZ concentration-time course profile for different dosage regimens. RESULTS: A total of 358 plasma BZN concentrations from 39 patients were included in the analysis. A one-compartment-PK-model characterized by clearance(CL/F) and apparent volume of distribution(V/F) with first order absorption(Ka) and elimination, adequately described the data (CL/F:1.73 L/h; V/F:89.6 L; Ka:1.15 h-1). No covariates were found to be significant for CL/F and V/F. Internal and external validation of the final model showed adequate results. Data from simulations revealed that a dose of 2.5mg/kg/12h might lead to overexposure in the most of the patients. A lower dose (2.5mg/kg/24h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3-6 mg/L. CONCLUSION: A population PK model for BNZ in adults with chronic Chagas disease has been developed. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24h would adequately keep BNZ trough plasma concentrations within the recommended target range concentrations for the majority of patients.