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Despite association between distress and worsened overall survival, little is known about specific causes of distress. The primary objective of this study was to identify stressors in patients with cancer receiving curative intent radiation therapy (RT) at a racially/ethnically diverse urban academic center. A secondary objective sought to evaluate the coping mechanisms used by these patients. This prospective, IRB approved, single institution, mixed methods study enrolled a pre-planned sample of 40 patients between 4/2021 and 2/2022. Distress was measured via the NCCN recommended Distress Thermometer (DT); specific stressors were determined using the Cancer Treatment and Distress Scale (CTDX) and coping methods using the Brief Cope (BC). All three questionnaires were completed prior to starting RT. Post-RT questionnaires and interview data is not yet mature and will not be reported here. DT was evaluated as both a continuous and dichotomized variable with a score of≥4 being distressed. Chi-squared, Wilcoxon rank-sum, and Pearson correlation tests were used, as appropriate, to assess these relationships. 39 patients completed study questionnaires. Patients predominantly self-identified as female (62%) and a minority (39% African American, 37% Hispanic). Of the 23 patients who reported their income, 52% had an annual income ≤$40,000. Most cancers were early stage (47% stage I-II) with the most common cancer types of breast (31%), prostate (23%), and gynecological (18%). 76% of patients reported feeling distressed (median 6, IQR 4-8). The strongest correlations between the DT and the CTXD, were related to health burden (physical limitations due to disease and treatment) (r=0.64, p<0.001) and uncertainty about the future/disease course (r=0.61, p<0.001). When evaluating coping strategies, higher DT scores (r=0.40, p=0.030) were associated with increased likelihood of using avoidant coping styles such as self-distraction, denial, and substance use. There was no association between feeling distressed and gender, race/ethnicity, income, receiving surgery or chemotherapy prior to RT, nor receiving concurrent chemoradiation. We found >75% endorsed clinical levels of distress, which is much higher than the ≤50% seen in predominantly white populations. These results suggest there is an opportunity to dramatically reduce distress in these economically disadvantaged cancer patients. Potential approaches for distress reduction could include targeted interventions such as pre-emptive rehabilitation medicine to improve physical function, an iterated education program based on patient understanding to ameliorate uncertainty, and mindfulness therapy to develop effective coping strategies. [ABSTRACT FROM AUTHOR]