Background This study aimed to establish a simple predictive model for oropharyngeal cancer (OPC) in an area with a relatively low prevalence of human papillomavirus (HPV) and frequent betel nut chewing. Methods A total of 116 patients with OPC were recruited from the clinical research database of a referral cancer center between 2013 and 2018. Patient characteristics—including age, gender, tumor stage, differentiation, and treatment modality—were extracted from the database. Patients diagnosed after 2018 were staged using the 7th AJCC staging system to explore the impact of extra-nodal tumor extension (ENE) on survival. Immunohistochemical analysis was performed for p16, epidermal growth factor receptor (EGFR), p53, and programmed cell death ligand 1 (PD-L1). ENE status was evaluated by pathological analysis or radiological features. Primary outcome was disease-specific overall survival (OS). Univariate and multivariate Cox regression were used to establish a predictive model. Results Mean age was 57.3 ± 9.9 years; 103 patients (88.8%) were male. P16 positive OPC was positively associated with higher PD-L1 and a tonsillar sub-site and negatively associated with betel nut chewing and cigarette smoking. In Cox regression, age, p16 status, EGFR, cT4, ENE, and cigarette smoking were significantly associated with OS. In survival tree analysis, cT stage was the most important risk stratification parameter, followed by EGFR expression and p16 status. Patients with cT4 stage or high EGFR were classified as the high-risk group and had poorest OS. Conclusions Due to the low prevalence of HPV and popularity of betel nut chewing in Asia, the relative importance of prognostic predictors for OPC are not identical to Western countries. Identification of significant prognostic biomarkers may improve treatment. Trial registration This study was registered and approved by the Institutional Review Board (IRB) of Kaohsiung Veterans General Hospital (VGHKS19-CT9-07; date of approval: Aug 9, 2019). Graphic Abstract