Osteoradionecrosis (ORN) of the jaws is a serious late complication of radiotherapy for head and neck cancer. Although HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct clinical entity with epidemiological and prognostic features, its relationship with ORN risk remains unclear. This study investigated whether tumor HPV status, assessed by p16 overexpression, influences ORN occurrence in patients treated with radiotherapy or chemoradiotherapy for OPSCC.

We performed a retrospective single-center cohort study at Gustave Roussy including patients treated with definitive radiotherapy or chemoradiotherapy for histologically confirmed OPSCC between January 2011 and September 2023. ORN cases were identified through structured and free-text screening of medical records and manually validated. The primary endpoint was cumulative ORN incidence, analyzed using a competing-risk model with death as the competing event.

Of 1142 eligible patients, 990 met the inclusion criteria: 519 (52%) had p16-positive tumors and 471 (48%) had p16-negative tumors. Median follow-up was 51.5 months. ORN developed in 111 patients. In univariable analysis, p16 status was not associated with the risk of ORN. After adjustment, p16 positivity was associated with higher adjusted ORN risk. Current smoking, alcohol use, peripheral arterial disease, and advanced T stage were also associated with higher ORN risk, whereas pre-treatment edentulism was protective.

In OPSCC patients treated with radiotherapy or chemoradiotherapy, p16 positivity was associated with higher adjusted ORN.