Importance: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is anticipated to rise over the next few decades until the effects of prophylactic vaccination are realized, which highlights the potential importance of secondary prevention. The objective of this review is to evaluate the evidence associated with screening for HPV-positive OPC. Observations: Evaluation of a potential clinical preventive screening service requires characterization of the disease burden, the at-risk target screening population, screening tests, treatment, and screening benefits and harms. The lifetime risk of OPC is 0.7% for men and 0.2% for women and is expected to increase. The disease burden of HPV-positive OPC is substantial; most patients undergo morbid multimodality treatment and incur high costs in the process. Middle-aged and older adult men with elevated number of lifetime vaginal or oral sex partners are at highest risk. Patients may benefit from early detection of the disease - the 4-year overall survival of patients with stage I HPV-positive OPC is 87%, a considerable portion of whom are eligible for less morbid single-modality therapy. However, available screening tests are insufficiently sensitive and specific considering the current HPV-positive OPC incidence rates in the most at-risk patients. Further, the benefits and harms of screening for HPV-positive OPC are unknown. Conclusions and Relevance: The current and projected future population-level burden of HPV-positive OPC supports further exploration of secondary preventive interventions. However, screening for HPV-positive OPC is not currently justified. Advances in biomarker discovery and improved characterization of (1) a highly at-risk, target screening population and (2) the benefits and harms of screening will be necessary. Large-scale clinical trials and rigorous evaluation of how to best implement this service into clinical practice will also be needed..
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