Most previous studies on the effectiveness of the first antiepileptic drug have dealt with adults. The present retrospective study of 520 patients was designed to investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug in children with newly diagnosed epilepsy. A total of 344 patients became seizure-free with the first prescribed antiepileptic drug. A lower proportion of patients with symptomatic epilepsy (60.3%) or cryptogenic epilepsy (61.5%) became seizure-free, compared with patients with idiopathic epilepsy (73.8%), and more patients with symptomatic or cryptogenic epilepsy changed their treatments owing to intolerable side effects. Most patients (95.6%) received sodium valproate (n = 234), topiramate (n = 143), or carbamazepine (n = 120). The majority of seizure-free patients required only a moderate daily dose. Patients who took carbamazepine (16.7%) or topiramate (11.9%) had a higher incidence of adverse events, necessitating a change of treatment, compared with patients treated with valproate (4.3%), and fewer of them became seizure-free. Overall, 66.2% of the patients became seizure-free with the first-ever antiepileptic drug, and most of them at a moderate dose. Moreover, tolerability was as important as efficacy in determining overall effectiveness.