Background: Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. Information on its prognostic value and its correlation with other relevant cancer related proteins is limited. Methods: We performed immunohistochemistry (IHC) analyses of p16, mutant p53 (mp53), and FGFR3 on 221 retrospectively collected OPSCC tissue samples. mp53, and FGFR3 were semi-quantified as weighted index [WI = % positive x intensity (0. 1+, 2+, and 3+)]. Correlations of FGFR3 WI with p16 status, and mp53 WI were analyzed. Association of FGFR3 with disease-free survival (DFS) or overall survival (OS) was assessed. Results: A total of 144/221 (65%) were p16 +, 93/172 (54%) had mp53, and 140/221 (63%) expressed FGFR3. FGFR3 was highly correlated with mp53 (p < 0.001), which was true in both p16 + and – OPSCC (p < 0.0001 and p = 0.0006, respectively).mp53 level was significantly lower in p16 positive versus p16 negative group (p < 0.0001). Univariate analysis revealed an association of p16 negative and high mp53 with worse OS (p < 0.001 and p < 0.001, respectively) and DFS (p < 0.001 and p = 0.004, respectively). FGFR3 was associated with worse OS and DFS (p = 0.014 and p = 0.047, respectively). On multivariable analysis FGFR3 was associated with worse DFS (p = 0.005), but not OS. Kaplan-Meier plot using medians of both FGFR3 and mp53 as the cut-off values showed that higher FGFR3 and mp53 correlated to worst DFS (p = 0.025) and OS (p = 0.009). Conclusions: Our results suggest that FGFR3 is associated with mp53 and p16 – OPSCC and correlates with worse clinical outcome. The biologic relation of FGFR3 and mp53 in OPSCC deserves further investigation. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).