The high prevalence of antiphospholipid antibodies (aPL) and antinuclear antibodies (ANA) in patients with epilepsy may be associated with either the disease itself or the antiepileptic treatment. The purpose of this prospective study was to determine the prevalence of aPL and ANA in children with idiopathic epilepsy before and during treatment with antiepileptic drugs. aPL, including both anticardiolipin and anti-β2-glycoprotein I antibodies, and ANA statuses were determined in 40 healthy children, 30 children treated with sodium valproate (VPA) monotherapy, and 20 children treated with carbamazepine (CBZ) monotherapy before and at 6, 12, and 24 months after treatment initiation. Fifteen children (50%) in the VPA-treated group and 7 (35%) in the CBZ-treated group showed positivity for aPL before treatment initiation, compared with only 4 of the 40 controls. Nine children (30%) in the VPA-treated group and 4 (20%) in the CBZ-treated group showed positivity for ANA before treatment initiation, compared with only 2 of the 40 controls. The subgroup analysis found nonsignificant associations at the different time points regarding the positivity of all of the autoantibodies. Only patients treated with VPA had a significantly decreased risk of aPL positivity after 6 months of treatment. The increased prevalence of autoantibodies in children with idiopathic epilepsy is strongly associated with the disease itself.