Source: Journal of Clinical Oncology Chaturvedi et al,1 analyzing specimens back to 1984, validate the long-held hypothesis that infection with human papillomavirus (HPV) has increased oropharyngeal squamous cell carcinoma (OPSCC) incidence in the US. They find the incidence of OPSCC in men—who have higher risks of both HPV-positive and HPV-negative OPSCC than women—similar to that of cervical cancer in women. From 1988 to 2004, incidence of HPV-negative OPSCC decreased in parallel with smoking whereas incidence of HPV-positive OPSCC increased at about 7.5% per year, so the percentage of OPSCC that was HPV-positive went from less than 20% to more than 70%. HPV-positive and HPV-negative OPSCC are etiologically and clinically distinct,2,3 with HPV-positive disease having better outcome.4–6 In the current study,1 the hazard ratio of 0.3 for HPV-positive/HPV-negative in survival analysis essentially balances the difference in prevalence so each form of OPSCC now accounts for a similar number of deaths. Notably, the authors found that outcomes for HPV-positive OPSCC have improved over time, whereas outcomes for HPV-negative OPSCC are as dismal as they were 25 years ago. The authors argue convincingly that vaccination to prevent oral HPV infections should be evaluated and that better treatments for both types of OPSCC should be developed. We are unlikely to get a better picture of the recent history of OPSCC in the United States. This study used all available OPSCC specimens from the three Surveillance, Epidemiology, and End Results (SEER) registries that participate in the Residual Tissue Repositories Program, analyzed them in several ways, [...]