Background: Evidence-based clinical guidelines for major depressive disorder (MDD) recommend stepped-care strategies for sequencing evidence-based treatments conditional on treatment outcomes. This study aims to evaluate the cost-effectiveness of stepped care as recommended by the multidisciplinary clinical guideline vis-à-vis usual care in the Netherlands. Methods: Guideline-congruent care as described in stepped-care algorithms for either mild MDD or moderate and severe MDD was compared with usual care in a health-economic state-transition simulation model. Incremental costs per QALY gained were estimated over five years from a healthcare perspective. Results: For mild MDD, the cost-utility analysis showed a 67% likelihood of better health outcomes against lower costs, and 33% likelihood of better outcomes against higher costs, implying dominance of guideline-congruent stepped care. For moderate and severe MDD, the cost-utility analysis indicated a 67% likelihood of health gains at higher costs following the stepped-care approach and 33% likelihood of health gains at lower costs, with a mean ICER of about €3,200 per QALY gained. At a willingness to pay threshold of €20,000 per QALY, the stepped-care algorithms for both mild MDD and moderate or severe MDD is deemed cost-effective compared to usual care with a greater than 95% probability. Limitations: The findings of our decision-analytic modelling are limited by the accuracy and availability of the underlying evidence. This hampers taking into account all individual differences relevant to optimise treatment to individual needs. Conclusions: It is highly likely that guideline-congruent stepped care for MDD is cost-effective compared to usual care. Our findings support current guideline recommendations.