OBJECTIVES: A cost-utility analysis of a new antidepressant, agomelatine (Valdoxan®) compared to generic fluoxetine and sertraline in the treatment of adult Major Depressive Disorders (MDD) was performed from the societal perspective and that of the Irish Health Service Executive (HSE). For each of these two perspectives, a separate analysis was performed for two different drug schemes: General Medical Services scheme (GMS) and the Drug Payments scheme (DP). METHODS: A Markov model was developed with health states for well, depressive episode, remission and death. The model also incorporated sleep disorders, discontinuation rates, discontinuation symptoms and adverse drug reactions. The time horizon of the analysis was two years. Remission, relapse and discontinuation rates as well as frequencies of the different clinical parameters were obtained from head-to-head comparative trials. Utility / disutility estimates were obtained from the literature. Costs (euros 2009) and effects were discounted at 4% per annum after year 1. RESULTS: From the societal perspective, agomelatine was dominant over both generic comparators in both drug schemes. From the HSE perspective, agomelatine was cost-effective compared to the two comparators in both drug schemes. One-way sensitivity analysis showed that the results were robust to uncertainty in model parameters. Probabilistic sensitivity analysis demonstrated that for a willingness-to-pay threshold of €45,000/QALY, agomelatine was cost-effective compared to the two comparators in more than 93% of cases for both drug schemes CONCLUSIONS: From the societal perspective, agomelatine was dominant over generic fluoxetine and sertraline for the treatment of adult MDD in Ireland. From the Irish HSE perspective, agomelatine was cost-effective compared to the two comparators with high probability.