['To determine the role of human papillomavirus (HPV) status on quality of life (QOL) in patients with oral cavity and oropharyngeal squamous cell carcinoma (OSCC). Since OSCC that are associated with high-risk HPV have an improved response to treatment and survival, we hypothesized that patients with these tumors would have better QOL trajectories.', 'Prospective cohort study.', 'Tertiary care academic medical center and 2 affiliated hospitals.', 'Head and neck-specific QOL was determined using the University of Washington Quality of Life scale version 4 in patients with newly diagnosed invasive OSSC (N = 228).', 'Pretreatment QOL was higher in patients with high-risk HPV-associated tumors compared with patients with HPV-negative or low-risk HPV-associated tumors (P = .015). Patients with high-risk HPV-associated tumors had larger decreases in QOL from pretreatment to immediate posttreatment compared with patients with HPV-negative or low-risk HPV-associated tumors (P = .041). There was no association between HPV status and 1-year posttreatment QOL.'] Do human papillomavirus-positive oral cavity and oropharyngeal cancer patients have better quality-of-life trajectories?