OBJECTIVES: To compare the cost-effectiveness of escitalopram with venlafaxine and generic citalopram and in the first-line treatment of Major Depressive Disorder (MDD) in Germany METHODS: A two-path decision analytic model with a 6-month horizon was adapted to the German setting using local clinical guidelines and data. All patients (aged = 18 years) started at the primary care path and were referred to specialist care in the secondary care path in case of insufficient response. Model inputs included drug-specific probabilities derived from a meta-analysis, clinical trials, published literature and expert opinion. Costs are calculated on the basis of German ex-pharmacy price for drugs, uniform remuneration scheme (EBM) for ambulatory care and diagnosis related groups (DRG: U63Z) for secondary care. Main outcome measures were success [Montgomery-Åsberg-Depression-Rating-Scale (MADRS) =12] and costs of treatment. The analysis was performed both from the German Statutory Health Insurance (GKV) and the societal perspective. The Human Capital approach was used to estimate the societal costs. RESULTS: From both perspectives, treatment with escitalopram yielded lower expected cost and greater success of treatment compared to generic citalopram. The expected success rate for escitalopram was higher (61.7%) compared to generic citalopram (57.7%). From the GKV perspective, the total expected cost per successfully treated patient was €149 (17.7%) lower for escitalopram (€694) compared to generic citalopram (€843). From the societal perspective, the difference was €463 between expected costs of €1.717 and €2.180, respectively. Escitalopram demonstrated a similar treatment success to that of venlafaxine at lower costs (€83 and €103, for GKV and societal perspective, respectively). Multivariate sensitivity analyses demonstrated the robustness of the results. In addition escitalopram shows a similar cost-effectiveness-ratio even at costs of £0 for generic citalopram (€694 vs. €691). CONCLUSION: Escitalopram is a cost-effective alternative compared to generic citalopram and venlafaxine in the first-line treatment of MDD in Germany