Background Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8 th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. Material and methods The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7 th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16(INK4a) or HPV-mRNA), p16(INK4a) positivity alone or the combination of HPV-DNA/p16(INK4a) positivity as diagnostic tests. Results A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16(INK4a) or HPV-mRNA), 83 (10.5%) were p16(INK4a) positive and 58 (7.4%) were double positive for HPV-DNA/p16(INK4a). ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16(INK4a)-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. Conclusion HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials.