OBJECTIVES: Most published cost-effectiveness analyses related to depression have used Markov models. However, evidence shows that probabilities of relapse and remission of depressive episodes are time and past events dependent, suggesting the appropriateness of discrete event simulation models (DESM). Our aim was to assess the cost-effectiveness of agomelatine in major depression from the Portuguese societal perspective using a DESM. METHODS: Sequential time to remission and time to relapse/recurrence were sampled from weibull distributions. Remission rates were obtained from a meta-analysis of randomized, venlafaxine-controlled clinical trials with either agomelatine, escitalopram, fluoxetine, paroxetine or sertraline. Probability of relapse/recurrence was assumed dependent on the number of previous depressive episodes and time since last remission. We compared agomelatine 25mg/day with possible dose titration to a mixed comparator composed by escitalopram(12mg/day), fluoxetine(38mg/day), paroxetine(25mg/day), sertraline(116mg/day) and venlafaxine(150mg/day), weighted according to the defined daily doses consumed between January and June 2008. Only direct costs were considered (drugs, medical visits, side effects treatments and monitoring). Effectiveness was measured in quality-adjusted life years (QALY) and life years in remission (LYR). Time horizon varied from 6 to 37 months according to each individual simulation characteristics. When appropriate discount rates of 5%/year were applied to costs and effectiveness. RESULTS: A gain of 9.4 QALY (95%CI:[6.2;12.4]) or 10 LYR (95%CI:[5.2;15]) was estimated for each 100 patients treated with agomelatine. The estimated incremental cost of agomelatine treated patients was €325 (95%CI:[-167; 827]). Corresponding incremental cost-effectiveness ratios were €3460/QALY or €3197/LYR. Probabilistic sensitivity analysis revealed 11% probability of agomelatine dominance and 97.5% of being cost-effective at a threshold of €10,000, regardless of the effectiveness measure considered. CONCLUSIONS: DESM is a valuable tool to model the cost-effectiveness of major depression. Agomelatine is a cost-effective drug for the treatment of major depressive disorder in Portugal, when compared to current clinical practice.