BACKGROUND Human papillomavirus (HPV) is a well‐established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non‐OP) head and neck squamous cell cancers (HNSCCs). METHODS This retrospective, multi‐institution study included OPSCCs and non‐OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non‐Hispanic, black non‐Hispanic, Asian non‐Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high‐risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan‐Meier and Cox proportional hazards models were used to evaluate overall survival (OS). RESULTS The study population included 239 patients with OPSCC and 621 patients with non‐OP HNSCC with a median follow‐up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non‐OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS. CONCLUSIONS For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non‐OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566–1575. © 2017 American Cancer Society. Among patients with oropharyngeal squamous cell cancer, the risk of death is reduced not only with human papillomavirus positivity (adjusted hazard ratio, 0.44; P = .007) but also for women versus men (adjusted hazard ratio, 0.55; P = .04). In contrast, among patients with nonoropharyngeal head and neck squamous cell cancer, the human papillomavirus tumor status (P = .77), p16 status (P = .26), and sex (P = .35) have no impact on overall survival. See also pages 1486‐7.