Background/Objectives Severe oral mucositis is widely viewed as a transient toxicity of antineoplastic therapy. Whether its long-term consequences differ between cancers that directly damage the upper aerodigestive tract (lip, oral cavity, pharynx [CLOP]) and systemic hematologic malignancies is unknown. To compare lifetime risks of mortality, dysphagia, malnutrition, respiratory disease, and cardiovascular disease in propensity-score-matched survivors of CLOP cancer versus leukemia with and without a history of ulcerative oral mucositis. Methods: Population-based retrospective cohort study using the TriNetX US Collaborative Network (90 healthcare organizations, >110 million patients). We identified 80,526 adults with a personal history of CLOP cancer (ICD-10-CM Z85.81) and 43,684 with leukemia (Z85.6) from 2005 to 2024. Cohorts were stratified by presence/absence of severe oral mucositis (K12.31 or K12.33 at any time). Separate 1:1 propensity-score matching was performed within each cancer type on age, sex, race/ethnicity, hypertension, diabetes, BMI, ECOG status, and external causes of morbidity. Exposures included documented severe (ulcerative) oral mucositis. Main Outcomes and measures were all-cause mortality and incident dysphagia, malnutrition, respiratory disease (J00–J99), influenza/pneumonia (J09–J18), and circulatory disease (I00–I99) after the index date. Results After 1:1 matching, 4,181 CLOP patients with mucositis were compared with 4,181 without, and 2,508 leukemia patients with mucositis were compared with 2,508 without. In CLOP survivors, mucositis was associated with markedly higher lifetime mortality (adjusted HR 1.94, 95% CI 1.87–2.01), dysphagia (HR 3.42, 95% CI 3.28–3.57), malnutrition (HR 2.81, 95% CI 2.66–2.97), any respiratory disease (HR 1.68, 95% CI 1.63–1.73), and influenza/pneumonia (HR 1.79, 95% CI 1.72–1.86). In leukemia survivors, mucositis conferred only modest or null excess risk (mortality HR 1.12, 95% CI 1.05–1.19; dysphagia HR 1.18, 95% CI 1.07–1.30; malnutrition HR 1.24, 95% CI 1.12–1.37; any respiratory disease HR 1.09, 95% CI 1.03–1.15). Conclusions and Relevance Severe oral mucositis is a powerful, durable prognostic determinant in cancers of the upper aerodigestive tract, where it identifies patients at dramatically elevated lifelong risk of swallowing dysfunction, aspiration-related lung disease, malnutrition, and premature death. The markedly attenuated effect in leukemia survivors suggests that direct high-dose radiation-induced structural damage to the pharynx and oral cavity—rather than systemic immunosuppression or chemotherapy intensity alone—is the dominant mechanism.