OBJECTIVES: Economic models have demonstrated the cost-effectiveness of escitalopram versus citalopram in major depressive disorder (MDD), but no head-to-head clinical trials have evaluated their cost-effectiveness to date. The objective of this study was to assess the relative cost-effectiveness of escitalopram compared with citalopram in outpatients with MDD. METHODS: An economic evaluation was conducted alongside a double-blind randomized clinical trial conducted by French general practitioners and psychiatrists, comparing fixed doses of escitalopram (20 mg/day) or citalopram (40 mg/day) over 8 weeks in outpatients with MDD (baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score ³ 30). A standardised healthcare services form was used to record physician visits, hospitalisations, treatments and days of sick leaves for the 2-month pre-study period and the 8-week study period. RESULTS: Statistically significant improvements in remission rates were observed in patients treated with escitalopram (56% vs. 43%, p<0.05). Using the price of the generic citalopram, mean per-patient costs from a healthcare perspective for the escitalopram group were 45% lower than the citalopram group (€79 vs. €144; p<0.05). Differences were mostly related to lower hospitalisation costs. Bootstrapped distributions of the cost-effectiveness ratios also showed better effectiveness and lower costs for escitalopram compared with citalopram with more than 85% of the draws located in the southeastern quadrant of the cost-effectiveness plan, indicating that escitalopram was the dominant strategy. Sensitivity analyses confirmed the dominance of escitalopram over citalopram from a payer perspective. CONCLUSIONS: Escitalopram is significantly more effective than citalopram and is associated with lower healthcare costs. This prospective economic analysis demonstrated that escitalopram is a cost-effective first-line treatment option for MDD.