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This study compared treatment outcomes in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments.This post-hoc analysis of data from a 6-month prospective observational study involving 1,549 major depressive disorder patients without sexual dysfunction focused on a subgroup of patients from East Asia (n = 587). Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16), whereas quality of life (QoL) was measured using EuroQoL instruments. PPS were rated using the modified Somatic Symptom Inventory. Multiple regression analyses were performed to compare the treatment outcomes.Duloxetine-treated patients had higher odds of achieving remission (odds ratio = 2.578, P < 0.001) and response (odds ratio = 2.704, P < 0.001) during follow-up, compared with SSRI-treated patients. They also had lower levels of disease severity and higher levels of QoL during follow-up. A similar pattern was observed in each subgroup of patients with and without PPS at baseline, but the effects of duloxetine relative to SSRIs were in general greater in patients with PPS.Patients treated with duloxetine had better treatment outcomes in terms of remission, response, depressive symptoms, and QoL, compared with SSRIs. Treatment with duloxetine may have additional advantages for patients with concurrent PPS.