Objectives/Hypothesis Literature examining long‐term survival in head and neck squamous cell carcinoma (HNSCC) with human papillomavirus (HPV) status is lacking. We compare 10‐year overall survival (OS) rates for cases to population‐based controls. Study Design Prospective cohort study. Methods Cases surviving 5 years postdiagnosis were identified from the Carolina Head and Neck Cancer Study. We examined 10‐year survival by site, stage, p16, and treatment using Kaplan‐Meier and Cox proportional hazard models. Cases were compared to age‐matched, noncancer controls with stratification by p16 and smoking status. Results Ten‐year OS for HNSCC is less than controls. In 581 cases, OS differed between sites with p16+ oropharynx having the most favorable prognosis (87%), followed by oral cavity (69%), larynx (67%), p16− oropharynx (56%), and hypopharynx (51%). Initial stage, but not treatment, also impacted OS. When compared to controls matched on smoking status, the hazard ratio (HR) for death in p16+ oropharynx cases was 1.5 (95% confidence interval CI: 0.7‐3.1) for smokers and 2.4 (95% CI: 0.7‐8.8) for nonsmokers. Similarly, HR for death in non–HPV‐associated HNSCC was 2.2 (95% CI: 1.7‐3.0) for smokers and 2.4 (95% CI: 1.4‐4.9) for nonsmokers. Conclusions OS for HNSCC cases continues to decrease 5 years posttreatment, even after stratification by p16 and smoking status. Site, stage, smoking, and p16 status are significant factors. These data provide important prognostic information for HNSCC. Level of Evidence 2 Laryngoscope, 129:2506–2513, 2019