OBJECTIVES: To determine the cost-effectiveness of escitalopram compared with citalopram in the management of severe depression (Montgomery-Åsberg Depression Rating Scale [MADRS] total score greater or less than 30) in the UK. METHODS: A decision analytic model with a 6-month time horizon was adapted from Hemels et al. (2004). The model incorporated treatment paths and direct resource use (psychiatric hospitalisations, medications, GP and psychiatrist visits, treatment discontinuation and attempted suicide) associated with the treatment of severe depression and indirect costs due to work absenteeism. Main outcomes were clinical success (remission [MADRS£12] at 6 months) and cost (2003 GBP) of treatment. The analysis was performed from both a societal and National Health Service (NHS) perspectives. Clinical data were derived from a meta-analysis of 8-week head-to-head randomised clinical trials and extrapolated to 6 months. Costs were derived from standard UK price lists and literature. Societal costs of lost productivity were calculated using the Human Capital approach. RESULTS: At 6 months after start of treatment, the overall clinical success remission rate was higher for escitalopram (53.7%) than for citalopram (48.7%). From the NHS perspective, the total expected cost per successfully treated patient was £146 (18.5%) lower for escitalopram (£786) compared with citalopram (£931). From the societal perspective, the total expected cost per successfully treated severely depressed patient was £238 (18.6%) lower for escitalopram (£1283) than for citalopram (£1521). Multivariate sensitivity analyses demonstrated that in >99% of the cases, escitalopram was dominant for both perspectives at all ranges of probabilities tested. Sensitivity analyses demonstrated that the model was robust and that, for the societal perspective, escitalopram remained the dominant strategy, even if citalopram had an acquisition cost of £0. CONCLUSIONS: The results of this study suggest that escitalopram is a cost-effective antidepressant compared with citalopram in the management of severe depression in the UK.