ABSTRACT: BACKGROUND:Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal squamous cell carcinoma (OPSCC), yet few studies have examined whether this association is modified by human papillomavirus (HPV) status. METHODS:Data from interviews and tumor HPV status from a large population-based case-control study, the Carolina Head and Neck Cancer Study (CHANCE), were used to estimate the association between oral health indicators and smoking among 102 HPV-positive patients and 145 HPV-negative patients with OPSCC and 1396 controls. HPV status was determined by p16INK4a (p16) immunohistochemistry. Unconditional, multinomial logistic regression was used to estimate odds ratios (ORs) for all oral health indictors adjusting for important covariates. RESULTS:Routine dental examinations were associated with a decreased risk of both HPV-negative OPSCC (OR, 0.52; 95% confidence interval [CI], 0.35-0.76) and HPV-positive OPSCC (OR, 0.55; 95% CI, 0.36-.86). Tooth mobility (a proxy for periodontal disease) increased the risk of HPV-negative disease (OR, 1.70; 95% CI, 1.18-2.43) slightly more than the risk for HPV-positive disease (OR, 1.45; 95% CI, 0.95-2.20). Ten or more pack-years of cigarette smoking were strongly associated with an increased risk of HPV-negative OPSCC (OR, 4.26; 95% CI, 2.85-6.37) and were associated less with an increased risk of HPV-positive OPSCC (OR, 1.62; 95% CI, 1.10-2.38). CONCLUSIONS:Although HPV-positive and HPV-negative HNSCC differ significantly with respect to etiology and tumorigenesis, the current findings suggest a similar pattern of association between poor oral health, frequency of dental examinations, and both HPV-positive and HPV-negative OPSCC. Future research is required to elucidate interactions between poor oral health, tobacco use, and HPV in the development of OPSCC. Cancer 2017;71-80. © 2016 American Cancer Society.