OBJECTIVES: To compare treatment outcomes in patients with major depressive disorder (MDD) treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI) for up to 6 months in a naturalistic setting in Mexico. METHODS: Data in this post hoc analysis were taken from a 6-month prospective, non-interventional, observational study that included a total of 1,549 MDD patients without sexual dysfunction in twelve countries (N=591 in Mexico). Depression severity was measured using the Clinical Global Impression (CGI) and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Pain was measured using the pain related items of the Somatic Symptom Inventory (SSI), and quality of life (QoL) was measured using the EQ-5D instrument with the UK population tariff and the EQ-VAS. Probabilities of initiating duloxetine (vs. SSRIs), expressed as propensity scores, were first constructed using logistic regression. Mixed effects modelling with repeated measures (MMRM) analysis was then used to compare treatment effectiveness and QoL between the duloxetine (N=168) and SSRI (N=413) groups, controlling for the propensity scores and other patient characteristics. RESULTS: The severity of depression was comparable between the two groups at baseline. Duloxetine-treated patients, however, had a higher level of pain severity and a lower level of QoL (EQ-5D) than SSRI-treated patients at baseline (p≤0.001). Both descriptive and MMRM regression analyses showed that patients treated with duloxetine had better outcomes during follow-up, compared with patients treated with SSRIs. At 6 months, duloxetine-treated patients had lower levels of CGI (2.25 vs. 2.52, p=0.005), QIDS-SR16 (3.95 vs. 5.35, p<0.001), and SSI-pain related (8.52 vs. 9.64, p<0.001), and higher levels of EQ-5D (0.92 vs. 0.87, p<0.001) and EQ-VAS (64.62 vs. 57.63, p=0.006) (MMRM results). CONCLUSIONS: Duloxetine-treated patients had better 6-months outcomes in terms of depression severity, pain and QoL, compared with SSRI-treated patients.