Objectives: 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. Design and subjects: This multiple-dose, fasting, randomised, two-period, cross-over 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. Results: 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. Conclusion: 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.