OBJECTIVES: Sexual dysfunctions (SD) is a common adverse event of antidepressants. It has a lasting impact on quality of life and is associated with an increased risk of early treatment discontinuation. Using an open-source Discrete Event Simulation model (https://open-model-mdd.org/), we performed a cost-effectiveness analysis comparing alternative sequences of treatments, to determine whether an antidepressant with moderate efficacy and reduced risk of SD should be positioned before or after a treatment with high efficacy and average risk of SD. METHODS: The model used was designed to simulate costs and QALYs in cohorts of patients with major depressive disorder (MDD), under alternative treatment strategies over 5 years. Each strategy consisted of up to 4 lines of treatment, with possibility to switch to different drugs when a patient experienced adverse events or lack of efficacy. We compared two strategies based on hypothetical treatments: under strategy A, an antidepressant with high response rate/high SD rate was prescribed in first-line and an antidepressant with moderate response rate/low SD rate available in second-line; under strategy B, the positions of these two drugs were reversed. Efficacy and safety parameters were obtained from a meta-analysis and other parameters, from the literature. Costs were estimated for the UK, from payer perspective. RESULTS: The numbers of QALYs were estimated at 3.660 QALYs (SE=0.013) and 3.649 (SE=0.012) under strategies A and B respectively. Costs were estimated at £3,894 (SE=60) and £3,918 (SE=61). CONCLUSIONS: Positioning an antidepressant with moderate efficacy and reduced risk of SD before or after a treatment with high efficacy and average risk of SD had no significant impact in terms of average costs and QALYs. Thus, differences in efficacy and tolerability can offset each other. In practice, the choice of first-line treatment should take account of patient preferences.