•Prolongation of the radiation course increased the hazard of death by 2% per day.•Prolongation >8 days was especially deleterious, while 1–3 days was not adverse.•Use of systemic therapy increased the risk of prolongation by 2-fold.•High facility volume (top quartile) decreased the risk of prolongation by 2-fold.•Other predictors included race, insurance status, comorbidity, and stage. To quantify the survival impact of prolongation of definitive radiotherapy (RT) for head and neck cancer in a national, modern cohort, and to identify predictive factors for prolongation. The National Cancer Database was queried for adults with non-metastatic cancer of the nasopharynx, oropharynx, larynx, or hypopharynx diagnosed 2004–2015, treated with definitive RT to 66–70 Gy in 30–35 fractions at 2–2.2 Gy per fraction. Multivariable Cox regression and propensity score matching were used to model the survival impact of RT prolongation, adjusting for potential confounders such as age and comorbidity. Predictors of RT prolongation were identified using multivariable multinomial logistic regression. In total, 36,367 patients were identified. As a continuous variable, RT prolongation increased the relative hazard of death by 2% per day (P < .0001). In the matched cohorts, patients with short (4–8 days) or long prolongation (>8 days) had lower absolute 4-year overall survival by 4% and 12%, respectively (P < .0001), while prolongation of 1–3 days was not significantly adverse. Major predictors of increased risk of prolongation were administration of systemic therapy, baseline comorbidity, lack of private insurance, and tumor/nodal stage. Conversely, higher facility volume was significantly protective, with a 55% lower risk of long prolongation within the topmost quartile (>11.5 patients/year). RT prolongation, especially >8 days, is significantly deleterious. Systemic therapy and facility volume were major predictors. Early identification of patients at increased risk of treatment interruptions may facilitate implementation of preventive measures.