INTRODUCTION: Non-small cell lung cancer (NSCLC) lung cancer continues to be a substantial issue in public health, and cardiovascular disease (CVD) is also an important cause of death in NSCLC patients. There is a lack of studies comparing the effects of surgery and radiation therapy on the risk of CVD mortality in patients with early stage NSCLC. This study planned to compare the effects of surgery alone and radiation therapy alone on the risk of CVD mortality in patients with early stage NSCLC. METHODS: In this cohort study, the data of 32,896 participants with NSCLC at stage I or stage II in 2010-2015 were retrieved from the surveillance, epidemiology, and end results (SEER) database. The primary endpoint of this study was CVD mortality, indicating patients died of CVDs and the follow-up was ended in 2020. Univariable Cox regression model was applied to identify covariates. The associations of surgery or radiation therapy with CVD mortality in in patients with early stage NSCLC were evaluated via univariable and multivariable Cox regression models and Fine-Gray competitive risk model. Hazards ratio (HR) and confidence interval (CI) were computed. RESULTS: The median follow-up time was 48.00 (17.00, 60.00) months. There were 854 (6.45%) participants died of CVD in the radiation therapy group and 729 (5.35%) participants died of CVD in the surgery group. After adjusting for confounding factors, the elevated risk of CVD mortality in patients with early stage NSCLC was observed in patients receiving radiation therapy compared to those receiving surgery (HR = 2.33, 95% CI: 2.02-2.69). In the competing risk model, the risk of CVD mortality in patients with early stage NSCLC was also increased in patients receiving radiation therapy (HR = 1.37, 95% CI: 1.2.6-1.55). In the PSM group, the risk of CVD mortality in patients with early stage NSCLC was also increased in patients who underwent radiation therapy (HR = 2.62, 95% CI: 2.12-3.24). Subgroup analysis also revealed that radiation therapy was correlated with increased risk of CVD mortality in NSCLC patients with tumor size ≥50 mm or <
50 mm, the original primary site in the left or right, histologic types of squamous cell NSCLC or adenocarcinoma NSCLC, stage I and II, and patients ≥65 years or <
65 years. CONCLUSIONS: Radiation therapy was associated with elevated risk of CVD mortality compared to surgery in patients with early stage NSCLC.