Background: The incidence of oropharyngeal cancer (OPC) due to tobacco and alcohol, respectively, has been declining, while that linked to human papilloma virus (HPV) has been rising. Epidemiologic, biologic, and prognostic characteristics of OPC differ by HPV-status. This study compared overall survival (OS) among HPV-positive and -negative patients with OPC in a real-world setting. Methods: This retrospective observational study used electronic medical records data from the Geisinger Health System to select patients diagnosed with OPC between January 1, 2010 and September 30, 2015. Patients were designated as HPV-positive if the HPV or P16 test closest to the diagnosis date was positive. All other patients were deemed HPV-negative. Descriptive statistics and relevant statistical tests were used to compare baseline characteristics by HPV status; survival by HPV status was examined using Kaplan–Meier methods and multivariable Cox models. Results: In this study, 152 patients met all selection criteria; 110 (72.4%) were HPV-positive. HPV-positive patients were more likely to be men (89.1% vs 73.8%; P=.019) and to have lymph node involvement (88.2% vs 59.5%; P=.0008); they were less likely to have cerebrovascular disease (6.9% vs. 23.5%; P=.01), or distant metastases (1.8% vs 9.5%; P=.029) vs HPV-negative patients. Among HPV-positive patients, 75.5%, 12.7%, and 10.9% had squamous cell carcinoma NOS, basaloid squamous cell carcinoma, and squamous cell carcinoma large cell non-keratinizing, respectively; corresponding values for HPV-negative patients were 85.7%, 0.0%, and 2.4%, respectively (P=.0013). HPV-positive patients were nominally younger than HPV-negative patients (median: 58 vs 61 years; P=.085). Log-rank test showed OS of HPV-positive patients (median OS from treatment initiation: not reached) is higher than of HPV-negative patients (median OS: 3.7 years; P=.002). In multivariable analyses, HPV-negative status was associated with increased mortality risk (P=.0035); other significant risk factors included alcohol use, diabetes, and distant metastases. Conclusions: HPV-positive status was associated with a decreased risk of mortality among OPC patients in this study. Despite the small sample size and potential violation of assumption of proportional hazard rate, this study underscores the prognostic implication of HPV status in OPC, which may have important ramifications in optimizing treatment decisions among this patient population.