OBJECTIVES The present cost-effectiveness analyses compare escitalopram versus duloxetine and generic venlafaxine in second-line MDD treatment, to inform decision-making on efficient second-line therapy choice. METHODS A decision model was based on second-line MDD treatment patterns (6-month timeframe). Effectiveness outcomes were sustained remission (the Montgomery-Asberg Depression Rating Scale (MADRS)≤12 at 2 months, sustained till the end of ,month 6) and quality-adjusted life years (QALY). Total cost included health care and absenteeism costs. Clinical inputs were derived from pooled analyses of randomized clinical trials on the second-line patients subgroup. Healthcare resource utilization was assessed from a Swedish observational cohort (HEADIS) and UK General Practice Research Database (GPRD). Utility estimates were based on HEADIS and US panel survey. Unit costs were from standard sources. Due to unavailability of generic venlafaxine unit cost, it was assumed equal to that of escitalopram in Scenario 1, and 5% of the brand venlafaxine cost in Scenario 2. RESULTS Over 6 months, a sustained remission rate was 56% for escitalopram and 38% for SNRIs (18% difference, 95% Credibility Interval (CrI) 0.8% to 32.9%)). The incremental QALY for escitalopram versus both comparators was 0.024 (95% CrI 0.006 to 0.042). Per patient savings with escitalopram versus venlafaxine were 670 USD (95% CrI 6689 to 4481) in Scenario 1 and US$565 USD (95% CrI -6588 to 4583) in Scenario 2. Versus duloxetine, savings were USD615, 95% CrI (6670 to 4554). With willingness to pay 42,500 USD (equivalent to 350,000 SEK) per QALY, escitalopram was cost effective versus venlafaxine with probabilities 86% and 61.7% in Scenarios 1 and 2, respectively, and with 85.4% probability versus duloxetine. CONCLUSIONS Escitalopram is cost-effective versus venlafaxine and duloxetine in second-line treatment of MDD in Sweden. The higher sustained remission rate and QALYs are associated with cost savings and support use of escitalopram following failure of first-line treatment.