OBJECTIVES: The objective of this study was to assess the cost-effectiveness (€ per quality-adjusted life year [QALY]) of all Selective serotonin reuptake inhibitors (SSRIs) and all Serotonin-norepinephrine reuptake inhibitors (SNRIs) for the treatment of Major Depressive Disorder (MDD) in Italy. METHODS: A decision analytic model was adapted from the Swedish Dental and Pharmaceutical Benefits agency model to reflect current clinical practice in the treatment of MDD in the largest Italian regions. This adaptation was possible thanks to the collaboration of an expert panel of Italian psychiatrists and health economists. The model evaluated patients with a first diagnosis of MDD and initiating an SSRI or an SNRI for the first time. The time horizon was 12 months. Efficacy and utility data for the model were retrieved from the literature and validated by the expert panel. Local data were considered for resource utilization and for treatment costs based on each regional health service perspective. Population-weighted regional data were used to define a national model. Scenario simulations, one-way sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model. RESULTS: The base case analysis showed that escitalopram was associated with a lower total cost (€1,562) and a larger health gain (QALYs) at one year (0.732) per patient, and dominated the other treatment strategies since more QALYs were achieved at a lower total cost. Sensitivity analyses support the robustness of the model. CONCLUSIONS: The results indicate that escitalopram is the most cost-effective pharmacological treatment strategy for the Italian health service compared with other SSRIs and all SNRIs used in the first-line treatment of MDD.