OBJECTIVES: To determine the economic impact of not using pharmacoeconomic analysis in the Brazilian National Drug Policy by measuring the cost-effectiveness of currently available antidepressants for major depressive disorder (MDD), and estimating the budget impact of using drugs, based on cost-effectiveness, compared to current Brazilian National Formulary drugs over 6 months from the Brazilian Ministry of Health viewpoint. METHODS: An existing decision tree model was adapted to Brazil based on practice guidelines. Clinical data were obtained from a published meta-analysis. Patients included adults =18 with MDD, diagnosed using DSM-III/IV, with moderate-to-severe disease (HAMD=15 or MADRS=18), without comorbidities/comedications, receiving =6 weeks of treatment with one of the following: venlafaxine, duloxetine, milnacipran, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, nortriptyline, or imipramine. Clinical outcome was remission (HAMD=7 or MADRS=12). Included were direct costs (drugs, physician visits, hospitalizations, etc.). Drug costs were obtained from the 2006 ANVISA Price List; resource utilization costs were taken from the National Healthcare System database (DATASUS) in 2007 Brazilian ‘Reais' (1R$=USD$0.47). Univariate and Monte Carlo sensitivity analyses tested model robustness. RESULTS: Cost-effective drugs by pharmacological group were: duloxetine, escitalopram, and nortriptyline. Duloxetine's expected cost/patient was lowest (R$3,872), followed by escitalopram (R$3,936), and nortriptyline (R$4,588). Average cost-effectiveness ratios were: duloxetine (R$4,624), escitalopram (R$4,790), and nortriptyline (R$5,866). Average cost–effectiveness for National Formulary drugs was R$7,710. The budget impact of replacing current listed drugs (amitriptyline, clomipramine, fluoxetine, and nortriptyline) by selected cost-effective drugs (listed above) would result in annual savings of >R$2.5 billion. Probability of savings were >90%. Monte Carlo analysis confirmed the results. Results were sensitive to variations in clinical rates. CONCLUSION: Cost-effective drugs dominated formulary drugs. Using newer drugs (while keeping nortriptyline) could save the Brazilian Ministry of Health >R$2.5 billion annually. Further analyses are warranted to study the impact of introducing pharmacoeconomic evaluations into policy decisions.