OBJECTIVES: To compare cost-effectiveness of Agomelatine versus Escitalopram-Venlafaxine matrix comparator in terms of Life Year in Remission (LYR) and Quality Adjusted Life Year (QALY).METHODS: A discrete event simulation hypothetical model was developed to describe the course of depressive disorders treatment in Thai setting. A sample size of 250,000 depressed patients and 1,000 simulations were generated. Antidepressants were analysed for treatment of acute phase (12-24 weeks), continuation phase (6-9 months) and maintenance phase (over 2 years of follow-up). Model was based on real Thai data, which acquired from public data, including disease parameters, costs of antidepressants, costs of medication treatments for insomnia and sexual side-effects, costs of cognitive behavioral therapy(CBT) and electroconvulsive therapy(ECT), mean costs of psychiatric visits and mortality data. Impact measures were derived from a systematic review and meta-analysis of international literature. Willingness to pay was set at 300,000 THB/QALY. Results were presented as costs (Thai Baht currency) per QALY and per LYR averted, compared to the matrix comparator which contained 41.8% venlafaxine-treated and 58.2% escitalopram-treated in real Thai data. Model simulation initiated with either Agomelatine 25 mg or a Matrix comparator (80% with Escitalopram 10mg , 20% with Escitalopram 20mg 20% or Venlafaxine150 mg). Relapse cases need treatment assumed addition of Sertraline, CBT and ECT.  RESULTS: The Incremental Cost-Effectiveness Ratios (ICER) of Agomelatine for episodic treatment either with or without a continuation of maintenance phase at base case was more effective than the matrix comparator by -177,008THB per LYR and -100,767THB per QALY. Probabilistic sensitivity analysis supported that Agomelatine was more cost effective than the matrix comparator at probability above 0.75.CONCLUSIONS: In Thai setting, Agomalatine was a more cost-effective treatment option for depressive disorders as compared to a matrix comparator of Escitalopram and Venlafaxine.