In adults newly diagnosed with epilepsy, treatment with the first prescribed antiepileptic drug fails for approximately one half. In two studies that addressed this question in children, the failure rates were 20% and 40%. The present study used a detailed chart review of children newly diagnosed with epilepsy over a 4-year span in a major childhood epilepsy referral clinic to assess (1) the percentage of children for whom first-line antiepileptic drug treatment failed and (2) the reasons for the treatment failure. Charts were reviewed for 95 children who were diagnosed with epilepsy, started on their first antiepileptic drug, and then monitored for approximately 5 years. Of these 95 children, 48 were classified as having idiopathic epilepsy (50.5 %), 30 as having cryptogenic epilepsy (31.6%), and 17 as having symptomatic epilepsy (17.9%). The two main antiepileptic drugs used were valproic acid (43.2% of patients) and carbamazepine (38.9% of patients). Treatment with the first antiepileptic drug failed in 30/95 children (31.6%). Treatment failure was due to adverse effects in 12/30 children (40.0%), due to lack of efficacy in 11/30 (37.9%), and due to both adverse effects and lack of efficacy in 7/30 (24.1%). Also examined was the effect on treatment failure of patient age at diagnosis, antiepileptic drug choice, maximum drug dose, etiology of epilepsy, and particular epilepsy syndromes on treatment failures; there was no statistically significant effect of any of these variables on first-line treatment outcome. In this population, approximately one third of children newly diagnosed with epilepsy experienced treatment failure with the first antiepileptic drug used. Lack of efficacy and unacceptable adverse effects contributed equally to these treatment failures.