Background/Objective: Body mass index (BMI) and treatment-related weight variation have been increasingly investigated as potential prognostic factors in head and neck oncology. However, their role in patients with oropharyngeal squamous cell carcinoma (OPSCC) undergoing concomitant chemoradiation (CRT) remains incompletely defined, particularly in real-world Eastern European populations. The aim of this study was to evaluate the prognostic significance of pretreatment BMI and treatment-induced weight variation in patients with OPSCC treated with curative-intent CRT and to assess their association with survival outcomes. Methods: This single-centre retrospective cohort study evaluated consecutive patients with OPSCC treated with CRT at a Romanian regional oncology centre between 2015 and 2023. Key exclusions were prior surgery or neoadjuvant chemotherapy, palliative care, and secondary malignancies. Clinical variables, baseline comorbidity burden (via Age-Adjusted Charlson Comorbidity Index), and body mass index (BMI) dynamics across treatment timepoints—including pre- and post-CRT BMI, ΔBMI during CRT, and weight loss thresholds ≥5% and ≥10%—were assessed. Overall survival (OS) was analysed using Kaplan–Meier curves, log-rank tests, and Cox proportional hazards multivariate regression to determine independent prognostic factors (p <0.05). Results: Among 114 patients analysed (median age 61; 80.7% male; median follow-up 52 months), 55.2% experienced ≥5% weight loss during chemoradiotherapy (CRT), and 22.8% lost ≥10%. On univariate analysis, significant predictors of reduced 5-year overall survival (OS) included age ≥65 years (HR 2.47, p = 0.01), CRT duration ≥ 47 days (63.2% vs. 92.3%; HR 2.52, p = 0.05), weight loss ≥ 10% (50.0% vs. 71.6%; HR 2.28, p = 0.03), pre-CRT BMI < 24 kg/m² (HR 0.50, p = 0.04), post-CRT BMI < 24 kg/m² (HR 0.40, p < 0.01), and a BMI reduction > 6% (HR 0.50, p = 0.03). On multivariate Cox regression, only age at diagnosis and CRT treatment duration were validated as independent prognostic factors for OS. Conclusions: Weight loss during concomitant CRT and low body mass index were associated with impaired 5-year OS in patients with oropharyngeal squamous cell carcinoma. However, after multivariate adjustment, age at diagnosis, and treatment duration were the sole independent prognostic factors.

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