The antiepileptic effect of allopurinol was assessed in a double-blind, randomized, placebo-controlled, cross-over trial in 84 patients with epileptic seizures refractory to standard antiepileptic drugs (AEDs). During a retrospective baseline period, patients experienced at least four seizures of any type per month. The effects of allopurinol and matching placebo were examined for 4-month periods. Allopurinol dosage was 150 mg daily for children weighing < 20 kg and 300 mg daily for other patients. Efficacy analysis based on the Wilcoxon rank-sum test was conducted for the 80 patients who completed the study. No significant period effect or treatment-period interaction was noted. Allopurinol significantly reduced total seizures (p = 0.005), and secondarily generalized seizures (p = 0.0015). Median seizure reduction for total seizures was 10.5 and 27.9% for secondarily generalized seizures. Subjective preferences by clinicians evaluated blindly significantly favored allopurinol. No significant change occurred in the plasma concentration of concomitant AEDs between treatment periods, but serum urate decreased by 32% during allopurinol treatment. No clinically relevant side effects or changes in routine laboratory clinical chemistry or hematology were ascribed to allopurinol.