To evaluate the prevalence of positive serum antinuclear antibody (ANA) in children with epilepsy using three major antiepileptic drugs (phenytoin, carbamazepine and ethosuximide), 60 children under 18 years with epilepsy who were referred to pediatric neurology clinic or had admitted to neurology ward in Children Hospital in Tehran, Iran, were entered our study. They had been treated with one of the three antiepileptic drugs (carbamazepin, phenytoin, ethosuximide) with suitable dose for at least one month. The patients were divided into two groups according to the classification of the International League Against Epilepsy (ILAE): drug-resistant and drug-responsive. We studied the epidemiological and clinical characteristics and also serum ANA of the patients in both groups. In this research, we studied ANA in 60 epileptic children. 30 patients were diagnosed with drug resistant epilepsy and the other 30 were drug responsive. None of them showed the clinical manifestations of lupus erythematosus. As a whole, 7 patients (11.7%) were ANA-positive, 6.7% of drug resistant and 16.7% of drug responsive group showed this finding. There was no relationship between drug resistancy and ANA according to statistical studies (P=0.21). Although in our study, epidemiological and clinical data of the patients was reported in two separate groups of resistant or responsive to antiepileptic drugs, and no meaningful statistical difference was found between these two groups. Overally in our study, the prevalence of positive ANA in patients receiving antiepileptic drugs was less in comparison with previous studies and was more common in males. Finally, we suggest a more comprehensive and extensive study with more cases and further follow-up period in order to find the cause of immunological reactions to antiepileptic drugs in children with epilepsy.