Background: Distress is common among cancer patients, and impacts morbidity and mortality. Head and neck cancer (HNC) is considered one of the most emotionally distressing of all cancers, and given the stark racial disparities in HNC outcomes, we sought to examine racial and sociodemographic factors associated with clinically meaningful distress in a cohort of patients with HNC. Methods: We built a retrospective cohort of patients at a semi-urban, academic, National Cancer Institute (NCI)-designated comprehensive cancer center in the Southeastern United States. Cohort included patients with a diagnosis of HNC who received care from the Radiation Oncology department 5 weeks or less of initial diagnosis, from 2017 to 2022. Outcome of interest was clinically meaningful distress, a binary variable defined as a score of ≥4 on the distress thermometer (DT), a validated tool measuring distress, with scores ranging from 0-10. Main independent variables were sociodemographic factors (race/ethnicity, age, sex, marital status, and health insurance status). We further adjusted for clinical variables (stage of presentation, anatomical subsites, smoking and alcohol history), and problem list domain items. Using chi-square tests and multinomial regression analysis, we estimated differences in distress and odds of meaningful distress by sociodemographic factors, adjusting for clinical factors and problem list domains. Results: From a primary sample of 1,167 patients, 507 patients met our inclusion criteria. Nearly half (45.8%) of our sample had clinically meaningful distress, with a median DT score of 3 (IQR, 0-6). Total number of problem list items and physical concerns showed significant racial differences (p< 0.05); however, in our final models, race was not significantly associated with clinically meaningful distress. Compared to those unmarried, married patients were significantly less likely to report distress (aOR = 0.62; 95% CI: 0.40, 0.95). Also, patients with emotional problems had double the odds of reporting clinically meaningful distress (aOR = 2.03; 95% CI: 1.02, 4.08). Other factors associated with significant clinical distress included tobacco history, and reported practical problems. Conclusions: Marital status and reported emotional problems are significantly associated with clinically meaningful distress in patients with HNC. Our study underscores the need for social support in mitigating distress and optimizing mental healthcare in our patient population. Further studies will explore distress trajectories across the HNC continuum and impact on HNC outcomes.