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Hospitalizations due to radiotherapy (RT) complications result in significant healthcare expenditures and adversely affect the quality of life of cancer patients. Using a nationally representative dataset, the objective of this study is to identify trends in the incidence of these hospitalizations, their causes, and the resulting financial burden. Data from the National Inpatient Sample was retrospectively analyzed from 2005 to 2016. RT complications were identified using ICD-9 and ICD-10 external cause-of-injury codes. The hospitalization rate was the primary endpoint, with cost and in-hospital death as secondary outcomes. 443,222,223 weighted hospitalizations occurred during the study period, of which 482,525 (0.11%) were attributed to RT. The 3 most common reasons for RT-related hospitalization were cystitis (4.8%, standard error [SE] = 0.09), gastroenteritis/colitis (3.7%, SE = 0.07), and esophagitis (3.5%, SE = 0.07). Aspiration pneumonitis (1.4-fold) and mucositis (1.3-fold) had the highest relative increases among these hospitalizations from 2005 to 2016, while esophagitis (0.58-fold) and disorders of the rectum and anus were the lowest (0.67-fold). The median length of stay of patient for hospitalization for RT complications was 4.1 (IQR, 2.2–7.5) days and the median charge per patient was $10,097 (IQR, 5755–18,891) and the total cost during the study period was $4.9 billion. Hospitalization for RT-related complications is relatively rare, but those that are admitted incur a substantial cost. Use of advanced RT techniques should be employed whenever possible to mitigate the risk of severe toxicity and therefore reduce the need to admit patients.