OBJECTIVES: To compare the costs and effectiveness of escitalopram with venlafaxine and fluvoxamine as first-line treatment of major depressive disorder (MDD) in Singapore from the societal perspective.METHODS: A decision analytical model was designed according to the disease management process in Singapore, consisting of two pathways, one for primary care and the other for secondary care. The time horizon was six months. The parameters in the model were derived from the published clinical trials and the results of a survey of local general practitioners and psychiatrists. The proportion of patients successfully treated (i.e., achieving remission, defined as MADRS score ≤12) was the main effectiveness outcome. Both direct and indirect costs were estimated in 2007 Singapore dollars. One-way and probabilistic sensitivity analyses were performed to test the robustness of the estimates. RESULTS: The overall success rate (MADRS £12) for six-month treatment was 68.1% for escitalopram compared to 66.0% for venlafaxine. The total costs per patient treated were $2845 for escitalopram compared to $3176 for venlafaxine. The overall success rate was 64.7% for escitalopram and 60.0% for fluvoxamine. The total costs per patient treated were $3133 for escitalopram compared to $3297 for fluvoxamine. Probability sensitivity analysis demonstrated that more than 95% of the samples fell in the lower-right quadrant of the cost-effectiveness plane, where escitalopram is dominant to venlafaxine and fluvoxamine. CONCLUSIONS: Escitalopram is a cost-effective pharmacotherapy as first-line treatment for MDD in Singapore compared to venlafaxine and fluvoxamine.