Our previous studies have shown the effectiveness of carbamazepine (CBZ) in the treatment of bipolar depression. This double-blind, randomized, placebo-controlled study was designed to further evaluate the efficacy of CBZ in unipolar depressed subjects who never received antidepressant and other psychotherapeutic treatment. A total of 89 patients who had at least two major depressive episodes, but never experienced mania or hypomania, were randomly assigned to treatment with immediate-release CBZ 300-800 mg/daily (n=51) or placebo (n=38) for 12 weeks. The primary efficacy was measured using the Hamilton Rating Scale for Depression (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression-Severity (CGI-S). The mean final CBZ dose of CBZ-treated patients was 461.6 mg/day. CBZ treatment yielded significantly greater improvements on the three efficacy measures at week 8 through endpoint compared to placebo. Patients assigned to CBZ treatment also had a significantly higher clinical response rate than placebo (74% vs. 42%, p<0.001), as defined for > or = 50% reduction in HAMD score. Based on the results of our present and previous studies, we suggest that CBZ might be considered an alternative in the management of certain conditions in major depressive disorder.