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p16 immunohistochemical expression serves as a surrogate for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). While HPV-positive OPSCC commonly demonstrates prominent nuclear expression, aberrant cytoplasmic expression has been demonstrated in tobacco-related head and neck cancers. The purpose of this study is to investigate the prognostic significance of p16 cellular localization in OPSCC.Retrospective cohort study and immunohistochemical expression analysis of 159 OPSCC patients treated at a tertiary-care Veterans Affairs Medical Center.All patients included in this study were male and the majority had significant tobacco (91%) and alcohol (88%) exposure. Overall, 57% of tumors were p16-positive, 32 (20%) subjects have tumors demonstrating low nuclear/low cytoplasmic (LN/LC) p16 expression, 29 (18%) high nuclear/high cytoplasmic (HN/HC) expression, 25 (16%) high nuclear/low cytoplasmic (HN/LC) expression, and 5 (3%) low nuclear/high cytoplasmic (LN/HC) expression. The 5-year disease-free survival (DFS) for the p16-negative group was 13.7%, compared to p16-positive LN/LC 28.4%, LN/HC 0%, HN/LC 74.7%, and HN/HC 93.1% (p<0.0001). Overall survival for the p16-negative group was 24.2%, compared to p16-positive LN/LC 23.5%, LN/HC 0%, HN/LC 74.2%, and HN/HC 88.7% (p<0.0001). On multivariable analysis, HN/HC and HN/LC expression patterns were associated with a statistically significant decreased risk of recurrence and death compared to p16-negative tumors.P16 localization has prognostic significance in OPSCC, with high nuclear expression associated with significantly better oncologic outcomes compared to low nuclear expression with high or low cytoplasmic p16 expression. P16 localization may provide additional insight into OPSCC carcinogenesis, particularly in patients with heavy tobacco exposure.