ObjectiveThe purpose of this study was to compare the efficacy and safety of escitalopram, paroxetine and venlafaxine in Korean patients with major depressive disorder (MDD).MethodsA total of 449 Korean MDD patients were recruited in a six-week, randomized, rater-blinded, active-controlled trial and were evenly randomized to paroxetine, venlafaxine, or escitalopram treatment.ResultsWhen comparing the mean difference for the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HDRS) total scores during six weeks, paroxetine (−6.4±0.4, and −5.4±0.4, respectively) was found to be significantly superior to escitalopram (−3.7±0.5 and −3.1±0.4, respectively). Venlafaxine had a significantly lower MADRS total score (−5.4±0.4) than escitalopram. When adjusting baseline variables, the response, according to the MADRS and HDRS scores, in the paroxetine group was greater than that for the escitalopram group (odds ratio [OR]=2.43, 95% confidence interval [CI]=1.42–4.16 for MADRS; and OR=2.32, 95% CI=1.35–3.97 for HDRS) and the venlafaxine group (OR=1.94, 95% CI=1.17–3.21 for MADRS; and OR=1.71, 95% CI=1.03–2.83 for HDRS). Despite that the overall tolerability was high and similar among the three groups, a total of 268 subjects (59.7%) prematurely discontinued treatment, representing the main limitation of the present study.ConclusionAlthough a low study completion rate limits generalizability, our findings suggest that paroxetine might be superior to escitalopram in Korean MDD patients. Further studies should be conducted to draw a definite conclusion.