INTRODUCTION: This study aims to assess the cost-effectiveness of the fall 2023 COVID-19 mRNA XBB.1.5 vaccination campaign in the Netherlands, comparing the XBB1.5 updated mRNA-1273.222 with the XBB1.5 updated BNT162b2 vaccine. METHODS: A 1-year decision tree-based cost-effectiveness model was developed, considering three scenarios: no fall 2023 vaccination, BNT162b2 vaccination, and mRNA-1273 vaccination in the COVID-19 high-risk population in the Netherlands. The high-risk population includes everyone of 60 and older, and younger adults at high risk as identified by the Dutch Health Council. Costs were included from a societal perspective and the modelled period started in October 2023 and ended in September 2024, including life years lost with a lifetime horizon. Sensitivity and scenario analyses were conducted to evaluate model robustness. RESULTS: In the base case, mRNA-1273 demonstrated substantial benefits over BNT162b2, potentially averting 20,629 symptomatic cases, 924 hospitalizations (including 32 intensive care unit admissions), 207 deaths, and 2124 post-COVID cases. Societal cost savings were €12.9 million (excluding vaccination costs), with 1506 quality-adjusted life years (QALYs) gained. The break-even incremental price of mRNA-1273 compared to BNT162b2 was €16.72 or €34.32 considering a willingness to pay threshold (WTP) of 20,000 or 50,000 euro per QALY gained. CONCLUSION: This study provides a comprehensive cost-effectiveness analysis supporting the adoption of the mRNA-1273 vaccine in the national immunization program in the Netherlands, provided that the Dutch government negotiates a vaccine price that is at most €34.32 per dose higher than BNT162b2. Despite limitations, the findings emphasize the substantial health and economic benefits of mRNA-1273 over BNT162b2 in the high-risk population.