Major depressive disorder (MDD) is a major public health issue. A Japanese community study showed prevalence as high as 20% compared to 17.1 % in the UK. MDD is largely under-diagnosed and under-treated in Japan as well as in Europe. Selective serotonin reuptake inhibitors (SSRIs) are effective treatment options for MDD. Given the scarcity of health resources, the evaluation of a new drug is not solely based on efficacy and safety, but also on its cost-effectiveness versus standard alternatives. OBJECTIVES: To assess the cost-effectiveness of escitalopram versus generic citalopram and fluoxetine, sertraline and venlafaxine in the treatment of depression in the United Kingdom. METHODS: A two-path decision analytic model with a 6-month horizon was used. Patients start on the primary path, and can be referred to specialist care on the secondary care path. Model inputs include drug-specific probabilities from comparative trials data, database analysis, the literature, and a panel of experts. The main outcome measure is success (remission), and costs of treatment (total and drug costs). RESULTS: The expected success rate was 62.7% for escitalopram, compared to 57.6% for citalopram, 57.6% for fluoxetine, 57.4% for sertraline and 60.0% for venlafaxine. Average expected total direct costs per patient were lower for escitalopram (£518) compared to generic citalopram (£579), generic fluoxetine (£591), venlafaxine (£585) and sertraline (£625). Budgetary impact shows a decrease in total Healthcare Budget estimated at £68 million 5 years after the introduction of escitalopram. CONCLUSION: Escitalopram can be considered to be the most cost-effective treatment alternative and advocating its use would reduce health care costs for the treatment of depression in the UK.