We report the results of a double-blind study comparing the efficacy and safety of low-dose (10-50 mg) and high-dose (20-100 mg) ranges of gepirone-extended release (ER) and placebo in 145 outpatients with major depressive disorder. At multiple time points and endpoint (Week 6), statistically significant reductions in Hamilton Rating Scale for Depression (HAM-D) scores were recorded for high-dose gepirone-ER compared to placebo. Analysis of the 17-item HAM-D and 28-item HAM-D scores indicated a relatively early onset of antidepressant efficacy with statistically significant results at treatment Weeks 1, 2, 4, and 6. A rapid response was evident in the high-dose group, beginning at Week 1 (p < .05). The most frequently reported adverse experiences were headache, nausea, dizziness, and insomnia. The results indicate that gepirone-ER is clearly superior to placebo in terms of antidepressant efficacy. When used at higher doses, gepirone-ER appears to be efficacious, safe, and well-tolerated in depressed out-patients.