Background <p>Studies on cost-effectiveness analysis of esophageal cancer are relatively common. However, there are few cost-effectiveness analyses that take a comparative approach between radiotherapy and surgery for esophageal squamous cell carcinoma (ESCC). A cost-effectiveness Markov model was constructed to explore the relationship between the benefits and costs of radiotherapy versus surgery for ESCC in China.</p> Methods <p>According to the observational data (patients’ medical records), 196 patients with ESCC enrolled for data were classified into surgery and radiotherapy two groups, both groups received preoperative and postoperative chemoimmunotherapy. A Markov model was constructed using TreeAge Pro Healthcare software to simulate the diseases progression after treatment. The model cost parameters were derived from the average treatment expenditures by real-world patients. The survival formula, fitted to real-world patient data in R, was used to calculate model transition probabilities.​ The utility value parameters were obtained by reviewing literature. Base-case, one-way deterministic sensitivity, and probabilistic sensitivity analyses were performed. The results were evaluated against willingness-to-pay (WTP) thresholds to determine the cost-effectiveness of treatments.</p> Results <p>Among 196 patients (131 males; 114 surgery group), median overall survival was 41.3 vs. 30.4 months and progression-free survival 28.0 vs. 20.6 months for surgery versus radiotherapy groups.​ Compared to radiotherapy, surgery had an incremental cost of 411,574.32 US dollars (USD), an incremental utility of 11.85 quality-adjusted life years (QALYs), and an incremental cost-effectiveness ratio of 34,744.52 USD/QALY, reaching 90% of the upper bound of WTP (three times the gross domestic product [GDP] per capita in China). One-way deterministic sensitivity analysis revealed that the costs of adverse event management and immunotherapy were key drivers affecting the incremental cost-effectiveness ratio. In probabilistic sensitivity analysis, at a WTP of 12,741.11 USD/QALY and 38,223.34 USD/QALY (1 to 3 times China’s per capita GDP), the probability of surgery being cost-effective was 10.1% and 62.5%, respectively. At a WTP of 33,080.09 USD/QALY, the probability was equal.</p> Conclusions <p>In China, Surgery was marginally cost-effective compared to radiotherapy for ESCC.​​ WTP thresholds, adverse reactions costs and immunotherapy costs constituted the primary factors influencing health economic evaluation outcomes in ESCC surgery versus radiotherapy.</p>