Epilepsy is a chronic disease; 30% of epileptic patients take more than one antiepileptic drug (AED) and therapy is usually lifelong. AEDs have a high potential for drug interactions due to their specific pharmacokinetic parameters: strong ability to induce or inhibit the cytochrome P450 system, which is the main route of drug metabolism; some of them have a narrow therapeutic range. A total of 18 AEDs were analyzed (8 of the first and 1 O of the second AED generation) of which 11 are registered in Croatia. Most of the clinically significant drug interactions among AEDs were two-way interactions. There were no clinically significant interactions among the second generation AEDs. The results show that there are considerably more clinically significant drug interactions with the first than with the second generation AEDs (88% : 12%). First generation AEDs have most clinically significant drug interactions with groups J, N and C of the Anatomical Therapeutic Chemical Classification of drugs. Most significant drugs with a high potential for interactions with antiepileptics from those groups are: calcium channel blockers - verapam il and diltiazem, amiodarone, doxycycl ine, macrolide antibiotics - erythromycin and telithromycin, metronidazole, protease inhibitors and selective serotonin reuptake inhibitors. Other noted groups of drugs of the Anatomical Therapeutic Chemical Classification that have clinically significant drug interactions with the first generation AEDs are oral contraceptives, anticancer drugs, cyclosporine and theophylline. Second generation AEDs have most clinically significant drug interactions with groups G and N of the Anatomical Therapeutic Chemical Classification of drugs, mainly with oral contraceptives.