BACKGROUND Felbamate is a new antiepileptic drug approved for partial and secondarily generalized seizures. METHODS Subjects with epilepsy (three men and seven women; age range, 20 to 39 years; weight range, 53 to 88 kg) who were previously stabilized with valproic acid, 9.5 to 31.7 mg/kg/day, received both 600 and 1200 mg felbamate twice a day in an open-label, randomized, crossover study. RESULTS Coadministration of 1200 or 2400 mg felbamate increased the mean valproic acid area under the curve (from 802.2 to 1025.4 and 1235.9 mg/hr/ml, respectively), peak concentrations (from 86.1 to 115.1 and 133.4 mg/ml, respectively), and average steady-state concentrations (from 66.9 to 85.5 and 103.0 mg/ml, respectively). No changes were observed in valproic acid time to peak concentration or protein binding. Average steady-state felbamate concentrations were 34.7 mg/ml for 600 mg administered twice daily and 61.2 mg/ml for 1200 mg administered twice daily. CONCLUSIONS When felbamate is added to a regimen of valproic acid, valproic acid doses may require reduction because coadministration of felbamate decreased steady-state valproic acid clearance (28% and 54%, respectively; p < 0.01).