OBJECTIVES: In 2009, 8,211 hospitalizations for major depressive disorder (MDD) occurred in Brazilian public hospitals, with mean duration of 20.5 days and average cost of 770BRL. To inform decision-makers about more efficient therapeutic strategies, this study aimed to compare costs of desvenlafaxine, escitalopram and duloxetine in the treatment of MDD inpatients from Brazilian public hospital perspective. METHODS: A decision tree model was built to assess costs of desvenlafaxine 50 mg/d, escitalopram 10 mg/d and duloxetine 60 mg/d to treat inpatients admitted due to MDD. Four health states were considered: remission, dose escalation due to lack of response, switching to another antidepressant after discontinuation caused by adverse event or failure, and treatment failure. This assessment assumes similar efficacy among alternatives due to lack of head-to-head clinical trials. Cost estimation assumed an 8-week time horizon. Relative risk of dropout versus placebo was obtained through systematic review. Only direct medical costs were considered and the cost components were drug acquisition costs and daily room charges. One-way sensitivity analyses were performed using drug prices, proportion of duloxetine patients requiring drug titration, and daily room charges (±20%) as key variables. RESULTS: Desvenlafaxine avoided 12% of estimated dropouts compared to competing alternatives. The estimated treatment costs were 1,955BRL, 2,213BRL and 2,476BRL per patient treated with desvenlafaxine, escitalopram and duloxetine, respectively. Therefore, desvenlafaxine exhibited  savings of -257BRL and -520BRL versus escitalopram and duloxetine, respectively. Within sensitivity analyses, the lower saving was observed when duloxetine titration was set as 0% (-94BRL versus escitalopram) and the higher when a +20% variation was applied to daily room charges (-580BRL versus duloxetine). CONCLUSIONS: Desvenlafaxine would be a cost-saving strategy compared to escitalopram and duloxetine in the treatment of patients admitted to the hospital due to MDD, given its lower price and lower dropout rates as a consequence of side effects.