The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open-label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2-fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20-kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 μg/kg/min in pediatric patients was comparable in performance to 2.0 μg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 μg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration—aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban.