OBJECTIVES: Comparing the cost-effectiveness of escitalopram with venlafaxine and generic citalopram and in the first-line treatment of Major Depressive Disorder (MDD) in the United Kingdom (UK). METHODS: A 2-path decision analytic model with a 6-month horizon was adapted to the UK setting using local clinical guidelines and data. All patients (aged greater than or equal to 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, GPRD database, published literature, and expert opinion. Unit costs (in 2003 GBP) were taken from the literature. Main outcome measures were success [i.e., remission defined as Montgomery-Åsberg Depression Rating Scale (MADRS) score less than or equal to 12] and costs of treatment. The analysis was performed from the National Health Service (NHS) and societal perspectives. The Human Capital approach was used to estimate the societal costs of lost productivity. RESULTS: From both perspectives, treatment with escitalopram yielded lower expected cost and greater success of treatment compared with generic citalopram. The expected success rate for escitalopram was higher (63.5%) compared with generic citalopram (58.2%). From the NHS perspective, the expected cost per successfully treated patient was £201 lower for escitalopram (£732) compared with generic citalopram (£933). From the societal perspective, the difference was £884 between expected costs of £3635 and £4519. Escitalopram demonstrated similar treatment success to that of venlafaxine at lower costs (£53 and £61, for NHS and societal perspectives, respectively). Multivariate sensitivity analyses demonstrated the robustness of the model and that escitalopram remained the dominant treatment option even at an acquisition cost of £0 for generic citalopram. CONCLUSIONS: Escitalopram is a cost-effective alternative compared to generic citalopram and venlafaxine in the first-line treatment of MDD in the UK.