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Objectives: The fibroblast growth factor receptor (FGFR) members including FGFR1–4 have been identified as promising novel therapeutic targets and prognostic markers in multiple solid tumors. However, the predictive role of the expression of FGFR proteins in oral squamous cell carcinoma (OSCC) requires further exploration. Materials and Methods: Immunohistochemical evaluation of FGFR1–4 was performed on 161 paired OSCC samples. The associations of FGFRs with clinicopathologic and prognostic parameters were analyzed. To further assess the contribution of FGFRs to OSCC proliferation, cell lines, and one PDX model was utilized to examine the anti‐tumor effect of the pan‐FGFR inhibitor AZD4547. Results: All FGFR members were found to be overexpressed in OSCC tumors when compared to normal tissues, and their expression was significantly associated with poor overall survival and disease‐free survival. Multivariate Cox regression analysis revealed high expression of FGFR1 (p = 0.014) and FGFR4 (p = 0.009) were independent prognostic factors and co‐overexpression of FGFR1 and FGFR4 with lymph node metastasis increased HR for death (p = 0.02). The pan‐FGFR inhibitor AZD4547 showed anti‐tumor activity in cell lines and in a patient‐derived xenograft of OSCC. Conclusions: This study highlights the co‐overexpression of FGFR1 and FGFR4 as a significantly poor prognosis indicator in OSCC when combined with lymph node metastasis. [ABSTRACT FROM AUTHOR]