OBJECTIVE The purpose of this study was to derive a population pharmacokinetics (PPK) model of lamotrigine clearance as well as to identify and describe factors that influence it in Serbian patients with epilepsy. METHODS A total of 40 steady-state serum concentrations from 38 adult and pediatric patients with epilepsy, collected during routine therapeutic drug monitoring, were used for the analysis. To determine the influence of different covariates on the estimate of lamotrigine clearance we built a non-linear mixed-effects one-compartment model with the first order elimination and without absorption. RESULTS Typical mean value of lamotrigine clearance, estimated by the base model (without covariates), in our population was 1.15 l h-1. The final model showed that lamotrigine clearance increased with total body weight, daily dose and concomitant administration of carbamazepine, and decreased with concomitant administration of valproate. The magnitude of carbamazepine and valproate effect was +1.13 l h-1 and -1 l h-1, respectively. The final model was validated in a group of 15 epileptic patients, showing good predictive performance. CONCLUSIONS The derived model describes well lamotrigine clearance in terms of characteristics of Serbian patients, offering basis for rational individualization of lamotrigine dosing regimens.