--- - |2+ Abstract Objective Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2‐year overall survival, and that relationships would be mediated by tumor response to treatment. Methods Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ‐9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2‐year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. Results Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089‐1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009‐0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848‐0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness‐survival relationship. Conclusions This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption—2 known prognostic indicators—to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality. - Psycho-Oncology, Volume 27, Issue 10, Page 2500-2507, October 2018.