OBJECTIVES: The objective of the present study is to determine the cost-effectiveness associated with three therapeutic classes for treating major depressive disorder (MDD) from the public healthcare payer perspective in Mexico. METHODS: To evaluate health and cost outcomes, a previously published decision model was adapted in order to reflect the usual treatment practice of MDD at the Institute for Social Security and Services for State Workers in Mexico (ISSSTE) during a 3-months time horizon. The three therapeutic classes included in the present analysis are: Selective Serotonin Reuptake Inhibitors (SSRI), Tricyclics (TCA) and Serotonin-Norepinephrine Reuptake Inhibitors (SSRI). Only direct medical costs were considered either generics or branded antidepressants with patent protection. All costs are presented in 2010 US dollars (Exchange Rate 1 US:12.50 MXN pesos) RESULTS: Within the three therapeutic classes assessed, the expected value for one patient with each three options was distributed as follows: $5 001, $4 215 $4 078 for group SSRI, TCA, and SNRI, respectively. The alternative with a greater expected remission rate was the SNRI class. For every thousand patients treated with SNRI, TCA, and SSRI, 725, 718, and 665 patients are expected to accomplish remission. For each thousand patients treated with SNRI instead of TCA, there will be $ 68 272 cost savings over a period of 3 months. Likewise, when compared against SSRI, the savings generated by SNRI is more than $ 367 437 for each thousand treated patients.  CONCLUSIONS: The results of the present analysis suggest that the SNRI as a therapeutic class in the treatment of MDD represent a dominant strategy.