OBJECTIVE: We conducted a multinational pharmacoeconomic evaluation of treatment for major depressive disorder (MDD) to assess the potential budget impact of changes in antidepressant prescribing patterns in Canada, Germany, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States and Venezuela. METHODS: The analysis compared the serotonin-norepinephrine reuptake-inhibitor (SNRI), extended-release venlafaxine, to selective serotonin reuptake-inhibitors (SSRIs) and tricyclic antidepressants (TCAs). A meta-analysis was performed to determine the clinical rates of success, defined as a 50% reduction in depression scores on the Hamilton Depression Scale (HAM-D) or the Montgomery-Asberg Depression Rating Scale (MADRS). Treatment regimen costs were determined from standard lists, fee schedules, and communication with local health economists in each country. We included data from 48 studies on 4,690 patients in the meta-analysis. The meta-analytic rates were applied to the decision analytic models to calculate the expected cost and expected outcomes for each comparator. Cost-effectiveness was determined using the expected values for both a successful outcome (as defined by the meta-analysis), and a composite measure of outcome termed ‘Symptom-Free Days’. A policy-analysis was conducted to examine the health system (budgetary) impact in each country of increasing the utilization of the most effective comparator. RESULTS: Treatment of MDD with extended-release venlafaxine yielded the highest overall efficacy rates for outpatients (73.7%) and inpatients (62.3%). Extended-release venlafaxine had the lowest rate of failure due to lack of efficacy (5.3%) and adverse drug reactions (11.3%). Initiating treatment of MDD with extended-release venlafaxine yielded the lowest expected cost for outpatients in 9 of the 11 countries studied, and for inpatients in 10 of the 11 countries studied. The weighted average expected cost per patient for MDD treatment varied from US$642 (Poland) to US$5,825 (US). The estimated budgetary impact to the primary payer for each 1% of utilization of extended-release venlafaxine ranged from US$61,640 (Switzerland) to US$1,565,900 (Germany) for each 1 million population. CONCLUSIONS: Policy-makers should implement measures to increase the utilization of cost-effective antidepressant treatment such as extended-release venlafaxine.