Background: The treatment of bipolar disorder in the depressed phase is complicated by a tendency for conventional antidepressant drugs to worsen the course of the illness by precipitating a manic episode or increasing cycle frequency. Thus, the potential antidepressant efficacy of mood stabilizers, such as divalproex, which is an effective treatment for the manic phase of bipolar disorder, is of considerable interest. Methods: The clinical efficacy of divalproex (valproate, Depakote®) was tested in an 8-week, double-blind, placebo-controlled, randomized clinical trial in 25 outpatients with bipolar I depression. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression, and secondary measures included the Hamilton Rating Scale for Anxiety, the Clinician Administered Rating Scale for Mania, and the Clinical Global Impression scale. Results: Using repeated measures ANOVA with last observation carried forward, divalproex was more effective than placebo in improving symptoms of depression (p=0.0002) and symptoms of anxiety (p=0.0001) than placebo. Limitations: The sample size was small, and most patients were male. Conclusions: These pilot results indicate that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar I, depressed phase. These positive results support the need to perform a larger, multisite study of divalproex treatment for bipolar depression. © 2004 Elsevier B.V. All rights reserved.