OBJECTIVES: To evaluate cost-effectiveness of escitalopram vs. duloxetine in MDD and to identify key drivers of costs in treatment of depression with escitalopram and duloxetine. METHODS: An economic evaluation was conducted alongside a double-blind, randomized study (escitalopram 20 mg/day and duloxetine 60 mg/day) in outpatients with MDD, aged 18–65 years, with Montgomery Asberg Depression Rating Scale (MADRS) ³26 and Clinical Global Impression Severity (CGI-S) ³4, and with reported baseline duration of depressive episode of 12 weeks-1 year. The main cost-effectiveness (CEA) analysis was conducted on the full analysis set (FAS), with all patients having =1 valid post-baseline health economic assessment. Additional analyses were conducted on completers set (CS) with complete follow-up data. Outcomes included Sheehan Disability Scale (SDS), MADRS total score, treatment response (MADRS decrease =50%) and remission (MADRS=12), and healthcare resource use and absenteeism from work evaluated by Health Economic Assessment. Unit costs of healthcare services were obtained from UK published standard sources. RESULTS: In the main CEA analysis on FAS, escitalopram appears to be more effective on the SDS scale (95% CI 0.10-3.74) and less costly than duloxetine (95% CI £-1.544 to -247). In additional analyses on CS, patients on escitalopram had 49% lower total cost compared to duloxetine (p=0.002), with sick leave contributing >73% of the total disease cost. Escitalopram was associated with 58% shorter sick leave duration compared to duloxetine (p<0.001). Patients with treatment response had 46% shorter sick leave (p=0.008), and those achieving remission, sick leave was 53% shorter (0.002). CONCLUSION: Escitalopram dominates duloxetine on the SDS scale, and is associated with significant cost savings compared to duloxetine. Treatment with escitalopram may reduce sick leaves duration through improved treatment response, and result in cost savings compared to duloxetine. The results are in line with other economic studies showing cost-saving with escitalopram compared to venlafaxine, another SNRI.