Background: Agents targeting the PD1/PDL1 pathway are currently under investigation for squamous cell cancer of the head and neck (SCCHN). We sought to explore the potential association of the PD1/PDL1 pathway with clinical characteristics, outcome and other biologically relevant alterations (EGFR, HER3, HER3) in SCCHN using an institutional patient and tissue database. Methods: Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) and or whole tissue sections (PD1/PDL1) using monoclonal antibodies. Expression of EGFR, HER2, HER3 was quantified in tumor cells while PD1/PDL1 was quantified on tumor cells, peritumoral stroma and stroma lymphocytes using intensity, percentage of positively staining cells and H-Score (product of intensity and percentage). Maximum PD1 lymphocyte density was measured on a scale of 0 to 4 (none, rare, moderate, high, very high). Significant associations (p < 0.05) between biomarkers and patient outcome were tested using descriptive and inferential statistics, logistic regression and Cox proportional hazards models in SAS 9.3. Results: We employed 100 OPSCC tissue samples for the analysis. Median age was 59 years, p16 positive (71%), male (81%), never smokers (18%), and 77% with stage 3 or 4. 25% of all cases were PDL1 positive. PD1 lymphocyte score of 2-4 was recorded in 65% of cases. There was a higher proportion of PDL1 (+) tumors in p16(+) OPSCC (87%) than PDL1 negative tumors (65%, p = 0.047). PDL1 status highly correlated with advanced nodal disease on multivariate analysis (5.53 (CI 1.06-28.77), p = 0.042). There was no correlation between PDL1, PD1 and EGFR, HER2, or HER3 expression. There was no association of PDL1 status with disease free or overall survival. Lower density of PD1+ lymphocytes in peritumoral stroma was associated with increased risk of death on multivariate analysis (HR = 3.17(1.03-9.78), p = 0.045). Conclusions: There was no association between PD1/PDL1 and expression of EGFR, HER2, or HER3 in OPSCC. PDL1 expression on tumor cells correlates with p16 positivity in OPSCC and advanced nodal status while low density of PD1 on peritumoral stromal lymphocyte density correlates with increased mortality.