OBJECTIVES: Depression has a lifetime prevalence of 10–25% among women and 5–12% among men. Selective serotonin reuptake inhibitors (SSRIs) are the most used and the most cost effective treatment in long-term MDD. Since the introduction of generic SSRIs the costs of the branded drug have been questioned. The objective of this study is to analyze the Cost-effectiveness of the most prescribed SSRIs: sertraline, paroxetine, citalopram, that lost their patent, and escitalopram that is still covered by a patent. METHODS: A decision analytic model was adapted from TLV (Dental and Pharmaceutical Benefits Board,  Sweden) in order to reflect the current clinical practice in depression helped by a panel of Psychiatrists and Health economists. Perspective used was the Lombardy Region Health Service and the Time horizon was 12 months. Several scenario simulations, one way Sensitivity analyses and Monte Carlo simulations have been performed in order to test the robustness of the model. RESULTS: Base case scenario showed an ICER of escitalopram vs. sertraline of € 4.395. All the tests showed that citalopram and paroxetine are dominated. One way Sensitivity analyses and tests were performed resulting in ICER variation from € 135 to € 18.000, nevertheless Monte Carlo simulations have shown an ICER stabilized at the mean value of around 4.000 euro confirming the base case scenario. CONCLUSIONS: ICER represents the additional cost due to a new technology related to its additional benefits. ICER has to be compared with a meaningful threshold value under which a technology may be considered cost-effective. Many agencies have studied this threshold. PBAC (Australia)  propose  € 25K, NICE (UK) propose € 35K. Comparing our base case scenario and also the ICER ranges that came from the Sensitivity analyses (One way and multivariate) with these thresholds escitalopram should be accepted as a cost-effective treatment for MDD.