Background: Prognosis and patterns of failure differ between HPV positive (pos) and HPV negative (neg) OPSCC. HPV neg have an increased risk of developing head, neck, and lung SPM due to field cancerization. Second primary OPSCC in HPV pos pts may be due to persistent risk for HPV-mediated carcinogenesis and compromised immune status. The rate and location of SPM in HPV pos pts is not as well described and HPV-specific surveillance guidelines are yet to be determined. Methods: Retrospective cohort study from a custom SEER database of OPSCC diagnosed from 2013-2015 was conducted. Differences in overall survival (OS) and SPM were compared by HPV status using Gray’s test. Cox proportional hazard models were performed, adjusting for age, race, sex, year of diagnosis, tumor grade, stage, and first treatment. Results: 12,895 pts were identified, with a mean age of 61.8 (SD = 9.97) years, mostly male (83.2%), and white (87.3%), with 45.0% HPV pos, 15.3% HPV neg, and 39.7% HPV unknown (unk). Proportion of HPV pos pts increased from 2013-2015 (40.7%-49.2%). HPV pos pts tended to have higher stage and grade of tumor. Most patients were treated with chemotherapy and radiation. Median duration of follow up was 13 (5-22) months. HPV pos had significantly lower unadjusted 2-year mortality compared to neg or unk (13.7% vs. 38.9% vs. 32.8%, p < 0.001). Median OS for HPV pos, HPV neg and HPV unk was 29 months (m), 25.6 m, and 24.45 m respectivey (p < 0.0001). From the multivariable Cox regression, HPV neg pts had 2.25 times the risk (95% CI: 1.99-2.54) of death compared to HPV pos pts. Incidence of OP SPM was similar (0.008-0.011%) in all three HPV cohorts (aHR = 0.87, 95% CI: 0.49-1.54). Conclusions: Our study strongly supports the prognostic value of HPV status. Incidence of OP SPM is similar in HPV pos and neg OPSCC suggesting that similar surveillance strategies should be employed for all OPSCC pts. Limitations of the study include lack of data on smoking and alcohol use, high rate of HPV unk pts, and SEER-imposed restriction to SPM occurring only in the OP region.