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Background: Vilazodone, a novel selective serotonin reuptake inhibitor and 5-HT1A partial agonist, was approved in 2011 for treatment for major depression. We aimed to compare the efficacy and safety of vilazodone versus escitalopram in patients with major depression at 4 weeks. Methods: Participants ( n = 52) were adult major depressive disorder outpatients who were randomized to receive either oral escitalopram (modal endpoint dose 20 mg/day; n = 26) or oral vilazodone (modal endpoint dose 40 mg/day; n = 26). Rater-blinded assessments of depression scores (primary outcome) and clinical severity of illness (secondary outcome) were obtained at baseline, 2 weeks, and 4 weeks. Adverse effects such as weight gain, sexual dysfunction, and diarrhea were recorded at each visit. The primary analysis was performed on the Intention-to-treat sample. Results: No significant difference was noted between groups on depression scores at study endpoint ( F = 2.80, df = 1,50, P = 0.10); however, the vilazodone group had significantly lower endpoint clinical severity of illness ( F = 7.69, df = 1,50, P = 0.01). At 2 weeks, there were no significant between-group differences on depression scores ( F = 0.006, df = 1,50, P = 0.94). Instances of diarrhea (P = 0.001) were significantly higher in the vilazodone group. Conclusion: Clinical ratings of major depression did not differ significantly between vilazodone and escitalopram groups at the end of 4 weeks. Our findings are limited by lack of statistical power to detect smaller differences between groups, should they exist.