Oral HPV16 infection is an established cause of oropharynx cancer, a cancer rising in incidence in the United States (U.S.), particularly among young, white men. Oral HPV16 infection confers an approximate 15-fold increased oropharynx cancer risk and has clear public health consequences. Yet, virtually nothing is known about the epidemiology of oral HPV infection. Our goal is to determine the prevalence and determinants (e.g. demographic, behavioral and health factors) of oral HPV infection in a representative sampling of the U.S. population. We hypothesize that differences in sexual behaviors by age, gender, race and birth cohort will account for patterns in oral HPV prevalence by these factors as well as for observed incidence patterns for HPV-related and HPV-unrelated HNSCC in the U.S. We have developed and validated methods for detection of oral HPV infection and demonstrated our ability to reproducibly detect infection over time. We have an established collaboration with the National Center for Health Statistics, the National Cancer Institute, and the Center for Disease Control and Prevention to perform a nested, cross-sectional study of oral HPV infection among 14 to 69 year old participants in the National Health and Nutrition Examination Survey (NHANES) 2009-2010, a population-based study designed to assess the health and nutritional status of the U.S. population. We now seek support to extend this study through 2014 to enroll the sample size necessary to achieve our aims, which are: (1) to determine the prevalence and type distribution of oral HPV infection in the U.S. population; (2) to identify demographic, behavioral and health factors independently associated with infection; (3) to evaluate the distribution of factors associated with oral HPV infection and HNSCC (e.g. sexual behavior, tobacco use, alcohol use, marijuana use) by age, gender, race and birth cohort and compare these to incidence patterns for HPV-related and HPV-unrelated HNSCC in the U.S. population. By accomplishing these aims, we will clarify the epidemiology of oral HPV infection, estimate the proportion of the U.S. population at risk for HPV-related HNSCC and identify birth cohorts at high risk. Our results may affect public policy or practice with regard to current HPV prophylactic vaccine policy for boys and will have future implications for the primary prevention of HNSCC via vaccination to prevent or screening to detect oral HPV infection.