Background: HPV positive squamous cell carcinoma of the oropharynx and tonsil has been associated with increased survival. However, the prognostic value of HPV status for other primary sites is unclear. We assessed the effect of HPV status on survival in patients with non-oropharyngeal head and neck squamous cell carcinoma at all stages. Methods: Data was obtained from the National Cancer Database (NCDB) to determine the effect of HPV status on overall survival (OS) in adults with non-oropharyngeal head and neck squamous cell carcinoma (gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx) using SAS software. Pearson’s Chi square test was used for comparisons by HPV status. The Kaplan-Meier method was used to estimate OS and differences were compared using a log-rank test. A multivariate Cox proportional hazards regression model analysis was performed to determine effects of individual variables on outcomes. Results: Patients with all stages of squamous cell carcinoma of the gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx diagnosed from 2010 to 2013 with complete HPV data were included (n = 13,908). In univariate analysis, HPV positivity, female gender, Asian race, primary site (lip, tongue, nasopharynx and hypopharynx), private insurance and any treatment (except for chemotherapy alone) were associated with increased OS, whereas increased age, Black race, higher Charlson-Deyo comorbidity score, hypopharynx primary, and higher AJCC stage were associated with worse OS. After adjustment for covariates, HPV positivity was associated with improved OS (HR 0.83, 95% CI 0.74-0.93; p < 0.001). Female gender, gum, lip, nasopharynx primaries, and private insurance on multivariate analysis predicted for improved OS, while age > 70, higher Charlson-Deyo score and higher AJCC stage were associated with worse OS. Conclusions: HPV positivity and female gender are good prognostic factors in squamous cell carcinoma of the head and neck, independent of primary site. Trials evaluating de-escalation of treatment should be considered for HPV positive tumors from non-oropharyngeal sites in the head and neck region.