To compare the bioavailability of divalproex extended release (divalproex-ER) given once daily relative to the conventional divalproex formulation given once every 8 hours, using various divalproex-ER doses that are 8-20% greater than the corresponding divalproex total daily doses. This multiple-dose, fasting, randomised, two-period, crossover design study in 76 subjects with epilepsy taking a concomitant enzyme-inducing antiepileptic drug compared the bioavailability of divalproex once-every-8-hours regimens with 8-20% higher daily dose divalproex-ER once-daily regimens. The 8-20% higher divalproex-ER once-daily-dose regimens were equivalent, with respect to exposure (area under the concentration-time curve; 1551 vs 1539 mg . h/L), to the corresponding total daily divalproex dose regimens. The divalproex-ER maximum concentration central value was significantly lower (83.3 vs 92.6 mg/L), and the minimum concentration mean was not significantly different (45.8 vs 44.8 mg/L) from the corresponding values for the divalproex regimen. The peak-to-trough fluctuation in plasma concentrations was significantly lower for once-daily divalproex-ER (64%) compared with once-every-8-hours divalproex (79%). The size of the divalproex dose and the presence of a concomitant enzyme-inducing antiepileptic drug did not have a statistically significant effect on divalproex-ER/divalproex relative bioavailability. No adverse event occurred in more than 5% of subjects on either treatment; all were mild or moderate in severity with none resulting in discontinuation. Both tested formulations were well tolerated by the subjects. This study demonstrated that patients with epilepsy taking divalproex may switch to 8-20% higher doses of divalproex-ER and have equivalent valproic acid exposure, lower fluctuation in valproic acid concentrations, and similar tolerability.