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To evaluate the impact of p16 expression as a surrogate marker of human papillomavirus status in oropharyngeal squamous cell carcinoma patients underwent surgery followed by postoperative radiotherapy.We identified 126 consecutive patients with histologically confirmed, newly diagnosed oropharyngeal squamous cell carcinoma who received surgery followed by radiotherapy and had p16 expression data available. All patients were treated between 2001 and 2011. Patients with high-risk factors (positive surgical margin and/or extracapsular extension) or other risk factors (multiple positive lymph nodes, perineural/lymphovascular invasion) were offered postoperative radiotherapy with or without concurrent chemotherapy.One hundred and four (82.5%) patients were p16-positive (p16 (+)) and 22 (17.5%) were p16-negative (p16 (−)). With a median follow-up of 56 months, patients with p16 (+) oropharyngeal squamous cell carcinoma exhibited a significantly better 5-year disease-free survival (80.7% vs. 57.6%, P < 0.001) and overall survival (84.9% vs. 59.1%, P < 0.001) than those with p16 (−) tumors. The p16 (+) oropharyngeal squamous cell carcinoma with high-risk factors (n = 64) showed no difference in disease-free survival (79.7% vs. 68.3%; P = 0.531) and overall survival (82.1% vs. 76.2%; P = 0.964) between postoperative radiotherapy and postoperative radiotherapy with concurrent chemotherapy.Expression of p16 is a strong independent prognostic factor of survival in the postoperative setting of oropharyngeal squamous cell carcinoma. The favorable prognosis of p16 (+) oropharyngeal squamous cell carcinoma suggests a need to re-examine traditional risk stratification for determining optimal adjuvant treatment.