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Purpose: Cancer diagnosis and treatment, including radiation therapy (RT), cause significant patient stress. Mindfulness and social support have been shown to help manage the psychological effects of cancer treatment. The objective of our study was to determine the sociodemographic and clinical factors associated with stress burden in patients receiving RT., Methods and Materials: Patients receiving RT for cancer at a single institution were given a 3-section survey to complete during the first on-treatment visit. The survey included the Perceived Stress Scale, Medical Outcomes Study Social Support Survey, and Mindfulness Attention Awareness Scale, which were used to measure stress, social support, and trait mindfulness, respectively. Linear regression analysis was performed to determine associations between perceived stress and age, patient sex, race and ethnicity, treatment intent, disease site, trait mindfulness, and social support. Factors significant in univariable analysis were analyzed with a multivariable analysis., Results: A total of 93 patients undergoing RT at a tertiary care academic institution were recruited from July to September 2019. Median scores for Perceived Stress Scale, Medical Outcomes Study Social Support Survey, and Mindfulness Attention Awareness Scale were 14.6 (range, 0-31; SD, 6.9), 4.2 (range, 1-5; SD, 1.0), and 5.1 (range, 3.1-6.0; SD, 0.8), respectively. On univariable analysis, mindfulness and social support were associated with decreased stress burden, and female sex and palliative intent were associated with increased stress burden. These factors all maintained significance in multivariable analysis., Conclusions: These results suggest measures to improve mindfulness and perceived social support, such as mindfulness meditation and psychoeducational approaches, may lessen the stress burden and improve quality of life for patients undergoing RT. Future studies should analyze the longitudinal impact of individual patient characteristics, including patient sex and treatment intent, to better understand their effects on psychological maladjustment during cancer care., Competing Interests: None., (© 2024 The Authors.)