Abstract Oral HPV is the cause of increasing incidence of HPV-related oropharynx cancer (HPV-OPC) in the United States and globally, and is expected to continue into the next century despite an effective vaccine. The risk of HPV-OPC and HPV-related anogenital malignancies is significantly increased among people living with HIV (PLWH). Oral and plasma HPV and E6 antibodies are associated with increased future risk of HPV-OPC and present an opportunity for screening for HPV-OPC. We have developed the longest running and largest cohort of healthy people living with and without HIV, with biomarkers of HPV-OPC. This study will combine our existing unique enriched cohort of individuals with HPV16 biomarkers with new participants identified in a screening scenario to develop a larger cohort of individuals at-risk for HPV16-OPC (called the MOUTH2 study). We will screen for oral and blood biomarkers with the aim to 1) study progression to HPV-OPC and how it differs in those with and without HIV; 2) characterize impact of HIV on oral HPV16 persistence, and 3) evaluate performance characteristics of stand-alone vs sequential biomarker screening. This prospective observational cohort will provide the ability to examine questions necessary to understand the long- term natural history of oral HPV in people living with and without HPV and to inform future study design to elucidate the benefits and harms of screening.