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Background Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) have a better survival than with HPV-negative oropharyngeal SCC. An 18F-fluorodeoxyglucose positron emission tomography-CT (18F-FDG-PET-CT) may also provide prognostic information. We evaluated glycolytic characteristics in HPV-negative and HPV-positive oropharyngeal SCC. Methods Forty-four patients underwent pretreatment 18F-FDG-PET-CT. Standardized uptake values (SUVs) and metabolic active tumor volumes (MATVs) were determined for primary tumors. HPV status was determined with p16 immunostaining, followed by high-risk HPV DNA detection on the positive cases. Results Twenty-seven patients were HPV-positive (61.4%). Median MATV was 2.8 mL (range = 1.6-5.1 mL) for HPV-positive and 6.0 mL (range = 4.4-18.7 mL) for HPV-negative tumors ( p < .001). SUV values are volume dependent (partial volume effect), therefore, MATV was included as covariate in multivariate analysis. In this multivariate analysis, the maximum SUV in HPV-positive tumors was 3.9 units lower than in HPV-negative tumors ( p = .01). Conclusion The 18F-FDG-PET-CT parameters are lower in HPV-positive than in HPV-negative patients. Low pretreatment SUV values in HPV-positive oropharyngeal SCC may be at least partly explained by HPV-induced tumor changes. © 2015 Wiley Periodicals, Inc. Head Neck 38: 529-535, 2016 [ABSTRACT FROM AUTHOR]