OBJECTIVES: Major depressive disorder presents a considerable burden of illness to patients, healthcare providers and payers. The introduction of SSRIs and SNRIs was noteworthy, but there are still patients who do not receive the full benefit of these drugs. Our objective was to assess the relative cost-effectiveness of escitalopram compared to venlafaxine XR in a randomised, double-blind, active-reference clinical study. METHODS: Outpatients fulfilling DSM IV criteria for a major depressive episode were randomised to receive escitalopram (10 to 20 mg/day; n=148) or venlafaxine (75 to 150 mg/day; n=145) in a double-blind study in a primary-care setting in Europe. In addition to clinical evaluations, assessments of generic quality of life (EuroQoL) were made at study entry and after eight weeks of treatment. Use of medical services and absence from work were recorded for the calculation of direct and indirect costs from the perspective of society and healthcare budgets. Multivariate modelling of costs controlling for patient characteristics was applied. For cost-effectiveness analysis, two efficacy measures were used (MADRS and EuroQoL). RESULTS: Statistically significant quality of life improvements from baseline were observed in both treatment groups, with no between-group differences. At the end of the study, escitalopram costs, compared to venlafaxine, were 10% lower (€747.5 versus €830.6) from a societal perspective, and 40% lower (€84.3 versus €141.5) from a healthcare perspective. Results of the multivariate model show that escitalopram tends to reduce direct costs (p=0.03). Bootstrapped distributions of the Incremental Cost-Effectiveness Ratios support the cost-effectiveness advantage of escitalopram. CONCLUSIONS: With similar effectiveness, escitalopram tends to lead to lower costs. These results are consistent with results of previous economic evaluation of escitalopram versus venlafaxine.