Abstract Background: It is unknown to what extent patient demographics, smoking, and alcohol use have contributed to changes in oropharyngeal and oral cavity cancer incidence rates. Methods: We performed a cohort study of Kaiser Permanente healthplan members, ages 20 to 89, for years 1995–2010 (n = 2.2 million annual members). Poisson Regression models estimated calendar trends in cancer rates both adjusted for and stratified by age, sex, smoking, and alcohol abuse history. Results: We identified 1,383 human papillomavirus (HPV)–related and 1,344 HPV-unrelated oral cavity and oropharyngeal cancer cases. With adjustment for age and sex, HPV-related cancer incidence rates increased 3.8% per year (P < 0.001) between 1995 and 2010, whereas rates for HPV-unrelated cancers decreased 2.4% per year (P < 0.001). For years 2007 to 2010, with additional adjustment for smoking and alcohol abuse, results were nonsignificant, but similar in magnitude. The increasing rates for HPV-related cancers were more prominent among nonsmokers (+14.5%) compared with smokers (−2.5%; P-interaction = 0.058). The decreased rates for HPV-unrelated sites were more prominent among those ≥60 years (−11.0%) compared with those <60 years (+16.8%; P-interaction = 0.006), among smokers (−9.7%) compared with nonsmokers (+8.4%; P-interaction = 0.055), and among those with an alcohol abuse history (−20.4%) compared with those without a history (+5.8%; P-interaction = 0.009). Conclusions: The observed increasing HPV-related cancer rates are most evident among nonsmokers, whereas the decreasing HPV-unrelated cancer rates are least evident among younger individuals, nonsmokers, and those without an alcohol abuse history. Impact: Continued vigilance for oropharyngeal and oral cavity cancer is warranted, including among those without traditional risk factors such as smoking and alcohol abuse. Cancer Epidemiol Biomarkers Prev; 24(6); 978–84. ©2015 AACR.