Epilepsy is one of the most prevalent chronic neurological diseases, affecting about 70 million people worldwide. Patients with epilepsy often encounter cognitive dysfunction, which is influenced by different factors including age at the onset of epilepsy, etiology of epilepsy, type of seizures, seizure frequency and duration, psychiatric comorbidity, and antiepileptic drug (AED) therapy. Event-related potentials are useful, noninvasive, objective clinical and research instrument for evaluation of cognitive functions in patients. The aim of this study was to investigate and determine the effect of AED monotherapy and polytherapy on cognitive changes in patients with epilepsy, detected with P300 event-related potentials and compared with age-and gender-matched healthy individuals. The study was conducted in 82 patients with generalized and focal epilepsy and 82 healthy individuals aged 18-65 years. Cognitive evoked P300 potentials were recorded in all study subjects using auditory 'oddball' paradigm. The results showed the patients taking AED polytherapy to have a significantly longer P300 latency and significantly lower N200-P300 amplitude. These results indicate that AED polytherapy might worsen cognitive impairment in patients with epilepsy.