Development of head and neck cancer (HNC) is associated with human papillomavirus high-risk (HPV-HR) types. The HPV E7 oncoprotein inactivates the pRB protein increasing expression of p16(INK4a). P16 expression and HPV status have been associated with differences in clinical outcomes for HNC. This study examined whether HNC prognosis was different when these biomarkers were examined as individual or joint molecular effects. Tumor tissue from 301 HNC patients were analyzed and sequenced for HPV types. P16 was evaluated by immunohistochemical staining. p16 was expressed in 35% and HPV-HR was detected in 27% of HNC patients. After adjustment for age, tobacco, and alcohol, p16+ tumors were statistically significantly associated with HPV-HR (OR=13.3, 7.1-24.9), histology, stage, grade, tumor site, and node involvement. Compared to p16+ HNC cases, those who did not express p16 had significantly worse disease-specific (DS) survival (Hazards Ratio, adj.HR=2.0. 1.0-3.9) and recurrence (adj.HR=3.6, 1.6-8.2); and HPV- cases had worse DS survival (adj.HR=2.8, 1.1-7.1) and recurrence (adj.HR=2.0, 0.8-4.8) compared to HPV-HR patients. Each of the p16/HPV groups had different survival outcomes: p16+/HPV-HR cases (referent) had the best and p16-/HPV- cases had the worst DS survival (adj.HR=3.6; 53% versus 13%, p=0.004) whereas p16+/HPV- and p16-/HPV-HR had similar DS survival (adj.HR=2.7/2.8). p16-/HPV-HR cases had a worse recurrence rate (adj.HR=7.0; 60% versus 0%, referent, p=0.08) than p16-/HPV- (adj.HR=4.5) or p16+/HPV- (adj.HR=1.8) cases. The combined p16/HPV biomarker data are associated with different survival outcomes of HNC compared to each marker evaluated separately, indicating that the two molecular mechanisms evaluated together may provide a more accurate prediction of clinical outcomes.