OBJECTIVES The purpose of the present study is to conduct an economic evaluation of Agomelatine vs the current alternatives in daily clinical practice for treating patients with major depression disorders (MDD) in Italy (Venlafaxine, Fluoxetine, Sertraline, Escitalopram and Duloxetine). METHODS Using a Markov model-based cost-effectiveness analysis, Agomelatine was compared with other therapies used for the treatment of MDD commonly prescribed (Venlafaxine, Fluoxetine, Sertraline, Escitalopram and Duloxetine), chosen on the basis of market shares, and compared with placebo. The population considered in the model consists of patients suffering from MDD and with an average age of 45 years. The perspective of the third party payer (Italian National Healthcare Service) and the societal perspective were considered.  RESULTS The study shows that Agomelatine administration is linked with higher direct and indirect costs only when compared with Duloxetine (respectively €4,365 vs. €4,253 and €5,553 vs. €5,484). Nevertheless, Agomelatine has the higher efficacy in terms of QALY gained (1.477) in comparison to all comparators considered in the analysis. According to the societal perspective, Agomelatine is dominant against Venlafaxine, Escitalopram, Fluoxetine and Sertraline, since it is less expensive and more effective and cost-effective compared to Duloxetine since the incremental cost per QALY gained is €12,461. According to the perspective of the Italian NHS, Agomelatine is dominant versus Venlafaxine, Fluoxetine and Sertraline and is cost-effective in comparison to Duloxetine (ICER 6,101 €/QALY) and Escitalopram (3,336 €/QALY). CONCLUSIONS The present economic evaluation indicates that Agomelatine provides greater benefit and is less costly compared to generic Venlafaxine, generic Escitalopram, generic Fluoxetine and generic Sertraline and that Agomelatine is cost-effective compared to Duloxetine. In conclusion, according to its favorable tolerability profile and its proven efficacy, Agomelatine represents a powerful tool for many patients suffering from MDD, which may lead to both clinical and economic advantages.