Objective – To determine the most cost-effective oral therapy for the treatment of Major Depressive Disorder (MDD) in Italy. Method – We conducted a pharmacoeconomic evaluation based on a decision analytic model that examined the treatment of major depressive disorder (MDD) in Italy. The analysis compared the serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine extended-release (venlafaxine XR), to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). A meta-analysis was performed to determine the clinical rates of success. The meta-analytic rates were applied to the decision analytic model to calculate the expected cost and expected outcomes for each anti-depressant comparator. Cost-effectiveness was determined using the expected values for both a successful outcome, and a composite measure of outcome termed ‘symptom-free days’. A policy analysis was conducted to estimate the financial impact to the Servizio Sanitario Nazionale (SSN). Results – Treatment of MDD with venlafaxine XR yielded the highest overall efficacy rates for outpatients (73.7%) versus SSRIs (61.4%) and TCAs (59.3%), and inpatients (62.3%) versus SSRIs (58.6%) and TCAs (58.2%). Venlafaxine XR had the lowest dropout rates due to lack of efficacy (4.8%) versus SSRIs (8.4%) and TCAs (6.8%), and adverse drug reactions (10.9%) versus SSRIs (17.4%) and TCAs (23.1%). Initiating treatment of MDD with venlafaxine XR yielded the lowest expected cost for outpatients and for inpatients. The total resulting savings for the SSN at a 5% venlafaxine XR utilization was estimated between L 963 million and L 3,210 million. Conclusion – This study confirms that venlafaxine XR is generally a cost-effective treatment of MDD. Additionally, the results of this investigation suggest that increased utilization of venlafaxine XR will favorably impact the SSN.