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Background/Objectives: Severe radiation-induced mucositis (RIM) is the most distressing acute side effect experienced by oropharyngeal squamous cell carcinoma (OPSCC) patients during chemo-radiotherapy (CRT), with a prevalence between 40 and 68%. RIM severity exhibits a multifactorial etiology that remains unclear. We aimed to analyze nutritional and morphofunctional predictive factors for severe RIM in OPSCC patients undergoing CRT. Methods: A prospective cohort study was conducted. Global Leadership Initiative on Malnutrition (GLIM) criteria, bioelectrical impedance vector analysis (BIVA), functional assessment and dosimetric analysis were performed prior to radiotherapy. Results: Eighty-two patients were analyzed. Severe RIM affected 46.3% of patients. Severe malnutrition according to GLIM (p = 0.011), prolonged Timed Up and Go (TUG) test (p = 0.025) and larger PTV54 volume (p = 0.049) were independent predictive factors for severe RIM, while higher fat-free mass (FFM) (p = 0.006) showed a protective effect. Conclusions: These findings highlight the importance of a comprehensive early nutritional assessment for accurately identifying patients at a higher risk of severe RIM.