Introduction: Triple-therapy with antiepileptic drugs (AEDs) is usually prescribed for epilepsy patients, whose seizures are not fully controlled with standard medications. Although 25 various AEDs are currently licensed for treating epilepsy, no algorithms allowing for the proper combination of AEDs are available. Objective: The aim of the study is to isobolographically assess the type of interaction among three AEDs (lacosamide [LCM], phenobarbital [PB] and valproate [VPA]), in the model of tonic-clonic seizures in mice. Material and methods: The electrically-evoked (25 mA, 500 V, 50 Hz, 0.2 s of stimulus duration) tonic-clonic seizures in male albino Swiss mice allowed determination of the anticonvulsant action of the three-drug mixture of LCM, PB and VPA combined in a dose ratio of 1:1:1 by means of type I isobolographic analysis of interaction. Results: The experimentally-determined ED50 exp value for the three-drug mixture was 112.04 mg/kg and did not differ from the theoretically calculated ED50 add value, which was 112.36 mg/kg. Lack of statistical significance confirmed that the mixture of LCM, PB and VPA in a dose-ratio of 1:1:1 exerted additive interaction in the mouse tonic-clonic seizure model. Conclusions: Although the three-drug combination of LCM, PB and VPA produced additive interaction in the mouse tonic-clonic seizure model, the three-drug combination could be recommended for epilepsy patients whose seizures are refractory to the standard medication.