We conducted a multi-national pharmacoeconomic analysis of oral therapies in the management of major depressive disorder (MDD) in ten countries located in Europe, Latin America, and North America. The study was performed by an independent group of researchers under an unrestricted grant from Wyeth-Ayerst Laboratories. Data used to populate country-specific decision analytic models were derived from an international meta-analysis, a Delphi panel (conducted in each country to ascertain local practice patterns), and a financial analysis to valuate resources consumed with local currencies. Health care system information was collected in order to model pharmacoeconomic and net economic endpoints. We performed a patient-level pharmacoeconomic evaluation of MDD using a decision analytic approach. We then applied the pharmacoeconomic results at the policy-level to calculate the net economic (budgetary) impact of shifting medical prescribing practice to the most cost-effective therapy. The perspective for the analysis was that of the public payor (i.e. government) for all countries studied except for the US, where the managed care perspective was evaluated. When weighted by population size, the 10-country average expected cost of treatment of major depression with venlafaxine is US$ 3,750 per patient, compared to US$ 4,460 for SSRIs and US$ 4,630 for TCAs. Thus, treatment of major depression with venlafaxine presents substantial per-patient cost savings compared to SSRIs (US$ 710) and TCAs (US$ 880). Direct costs evaluated include the cost of pharmacuetical agents, physician services, laboratory services and hospitalization. The expected cost savings attributible to venlafaxine are a function of a reduced requirement for health care services. The net economic impact of a 1% shift in venlafaxine utilization in the 10 countries studied translates to a savings of US$ 14.24 million in total direct cost to society and a US$ 7.74 million in direct cost to the primary payers. The results withstand comprehensive sensitivity analysis.