--- - |2+ Abstract Objective Depression is a significant problem for patients with head and neck cancer (HNC). This study explored the prevalence of and sociodemographic and clinical factors associated with depression, among patients with HNC. Methods We performed a retrospective analysis of 71 541 cases of HNC using a national dataset, the Nationwide Inpatient Sample, from 2008 to 2013. Weighted, multivariate logistic regression analysis estimated association between sociodemographic/clinical factors and tumor anatomical site with diagnosis of a major depressive disorder. Results Overall prevalence of major depressive disorder in HNC was 9.3%; highest prevalence was found in patients with laryngeal cancer (28.5%). Compared with laryngeal cancer, there were lower odds of depression among patients with oral cavity cancer (adjusted odds ratio [aOR] = 0.90; 95% CI, 0.84‐0.97) and other anatomic sites (aOR = 0.87; 95% CI, 0.81‐0.94), except oropharyngeal cancer (aOR = 1.00; 95% CI, 0.93‐1.08). For every unit increase in comorbidities, odds of depression increased by 20% (aOR = 1.20; 95% CI, 1.19‐1.23). Sociodemographic factors associated with increased odds of depression included being female (aOR = 1.77; 95% CI, 1.68‐1.87), white (aOR = 1.75; 95% CI, 1.59‐1.92), and having Medicaid (aOR = 1.09; 95% CI, 1.01‐1.19) or Medicare insurance (aOR = 1.19; 95% CI, 1.10‐1.27). Conclusions Depression odds vary depending on HNC anatomic site, and one in four patients with laryngeal cancer may be depressed. Since depression is prevalent in this survivor cohort, it is important that psychosocial assessment and intervention are integrated into mainstream clinical care for patients with HNC. - Psycho-Oncology, EarlyView.