The rate of vaccination against human papillomavirus (HPV) among adolescent girls and boys over the past few years has been stagnant in spite of the increase in incidence of HPV-positive oropharyngeal (OPX) squamous cell carcinoma (SCC). The indirect relationship between HPV cancer incidence and preventive vaccination poses a public health concern and has caused clinicians to search for other methods toward eradicating the ongoing oropharyngeal carcinoma epidemic. This alarming increase in OPX is motivating a search for therapeutic prevention strategies, including biomarker discovery, risk assessment, therapeutic vaccines, immunotherapy, and surgery. The current Danish Cancer Registry study by Fakhry and colleagues (in this issue) is the first to investigate the impact of prior tonsillectomy on the development of HPV OPX. They report that remote tonsillectomy resulted in a decreased incidence of tonsillar SCC. While thought-provoking, this study has a small sample size. Also, tonsillectomy does not address all anatomic sites at risk; there is lack of well-defined precancerous lesions or biomarkers to identify high-risk patients, and cost and morbidity make it impractical to justify prophylactic tonsillectomy as a cancer preventive strategy at present. The provocative clinical signal reported in this study supports further research and strategies that employ surgery when the technology and epidemiology can reliably be used to identify high-risk subjects.