Divalproex sodium is an effective anticonvulsant, antimanic, and migraine prophylaxis agent. Recently, a new extended-release (ER) formulation of divalproex sodium has become available, which allows for once-daily dosing and provides prolonged therapeutic serum levels. Using data pooled from nine open-label trials involving 321 epilepsy and psychiatry patients, we compared the efficacy and tolerability of divalproex ER with preceding treatment with the older delayed-release (DR) formulation, based on patient reports and analysis by McNemar's test for within-subject paired data. Divalproex ER was associated with superior tolerability with less frequent tremor, weight gain, and gastrointestinal complaints (all P<0.001), but not less hair loss. Divalproex ER also yielded improved seizure control and greater improvement of psychiatric symptoms, and was greatly preferred by patients over divalproex DR. Although the results of the current analyses must be considered highly tentative due to the open-label nature of the trials included, the findings do suggest broad clinical superiority of the new ER preparation.