Background: Epithelial growth factor receptor (EGFR) is overexpressed in squamous cell carcinoma of the head and neck (SCCHN) and is a therapeutic target for this disease. Since other members of the HER receptor family may be valid therapeutic targets in SCCHN we examined the expressions of EGFR, HER2, and HER3 and correlated their expression with clinical patient characteristics. Methods: After IRB approval 96 patients with OPSCC had tissue and clinical information collected and analyzed. Tissue microarray stained by immunofluorescence (IHF) was used to evaluate HER receptor expression. High risk HPV status and p16 status were determined by HPV DNA in situ hybridization (ISH) and immunohistochemistry (IHC) staining, respectively. The correlation with clinical characteristics of each receptor and their effects on disease-free survival (DFS) or overall survival (OS) were assessed. Results: p16 status was inversely correlated with EGFR expression (P=0.012), whereas no significant association between p16 status and HER2 or HER3 expression was found (P= 0.563 and 0.635, respectively). Current smokers had the highest EGFR expression compared to never or former smokers (P= 0.006). Patients with T3 and T4 disease had a higher EGFR expression compared to T1 and T2 disease (P= 0.040). HPV negative smokers had a significantly higher HER2 (P = 0.043) and HER3 expression (P = 0.019) compared to non-smokers. Among patients with low EGFR expression, HPV negative patients had a higher HER3 expression compared to HPV positive patients (P = 0.048). Patients with high EGFR expression were more likely to have disease progression (HR: 1.58; 95% CI: 1.13 – 2.20; P= 0.007) or death (HR: 1.30; 95% CI: 1.01 – 1.68; P=0.042). HER2 or HER3 expression were not related to DFS or OS in OPSCC. Conclusions: EGFR was a prognostic factor for worse DFS and OS in OPSCC. Among patients with low EGFR expression HER3 expression was higher in HPV negative patients. These findings may point to a role for combined EGFR and HER3 targeted therapy in HPV negative disease, but will need to be confirmed in other studies. (This study was supported by a grant from Merrimack Pharmaceuticals to NFS and GZC).