It is unknown to what extent patient demographics, smoking, and alcohol use have contributed to changes in oropharyngeal and oral cavity cancer incidence rates. We performed a cohort study of Kaiser Permanente health plan 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. 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). 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. Continued vigilance for oropharyngeal and oral cavity cancer is warranted, including among those without traditional risk factors such as smoking and alcohol abuse.