Windon MJ, D'Souza G, Waterboer T, et al. - This is the first study investigating risk factors of patients with HPV-positive nonoropharyngeal (HPV-nonOPC) compared with HPV-positive oropharyngeal (HPV-OPC) squamous cell cancers. Incident cases of HPV-positive head and neck cell cancer and matched non-cancer controls were registered in a multi-institutional, prospective study investigating risk factors, biomarkers, and survival. According to this prospective, case-control and case-case comparison, HPV-nonOPC (n = 20) were more likely to be ever smokers than controls (n = 80) and HPV-OPC (n = 185). In terms of behavior, biomarkers, comorbidity, and prognosis, nonoropharyngeal cancers with confirmed HPV oncogene expression were found to be distinct from HPV-positive oropharyngeal cases.