Summary. Therapeutic drug monitoring of anti-epileptic drugs is widely used for the management of epilepsy and to avoid treatment ineffectiveness or to explain the onset of adverse events. In this study, we explored the role of months and seasons of withdrawal for the plasma quantification of oxcarbazepine, lamotrigine, phenytoin and levetiracetam pharmacokinetics and the prediction of the outcome cut-offs. One hundred and seventy-five adult patients were enrolled. Drugs plasma concentrations were measured by HPLC-UV methods. We reported that oxcarbazepine concentrations in autumn and winter were higher than those registered in spring and summer. In a logistic regression model, warm seasons have been considered as predictive factors of a negative therapeutic range. If we separately evaluate males and females, the influence of seasons on oxcarbazepine concentration remains only in male patients, also considering the logistic regression analysis. No factors significantly influenced lamotrigine, phenytoin and levetiracetam concentrations or were considered in regression models as predictive factors of treatment outcomes. These results suggest for the first time the effect of seasons on oxcarbazepine. Applying a seasonal- and sex-specific approach should be the key to optimize treatment in each patient, in each period of their life.