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Background: Major depressive disorder (MDD) is a common psychiatric disorder that 16.2 of population in developed countries experience it at least once in their lifetime; it is a major cause of social disability according to WHO reports. This study was designed to compare the efficacy of fluvoxamine and sertraline in treating major depressive disorder. Methods: During this randomized clinical trial, 110 patients with certain diagnosis of major depressive disorder were divided in two parallel groups: fluvoxamine 200 mg daily and sertraline 100 mg daily. Beck test was done before and after intervention and the data were analyzed by chi-square and independent-sample t tests. Findings: 58 patients (52.72%) received fluvoxamine and 52 (47.28%) received sertraline. Fluvoxamine had better therapeutic effects than sertraline (P = 0.002). Although, women (P = 0.007) and age group of 43-67 years (P = 0.015) had better response to fluvoxamine. Conclusion: According to current findings, it is recommended that gender and age group be noticed in administrating the selective serotonin re-uptake inhibitors (SSRI) drugs in patients with major depressive disorder.