Objective To investigate the expression and biological significance of EphA2 and VEGF protein in tissue specimens of laryngeal squamous cell carcinoma (LSCC), and further study the correlation between the protein expression of EphA2 and VEGF. Methods The expression of EphA2 and VEGF protein was evaluated by immunohistochemical staining in 69 cases of LSCC specimens and 15 cases of adjcent epithelial tissue samples, and their correlation with clinicopathologic parameters was analyzed. Results The positive rates of EphA2 and VEGF in LSCC tissues were significantly higher than those in adjacent noncancerous mucosa (P<0.05), and the expression of these two marks was closely correlated with clinical stage (P<0.05) and metastasis (P<0.05) in patients with LSCC. Furthermore, the expression of EphA2 was also associated with tumor site (P<0.05). However, the expression of EphA2 and VEGF had no significant association with age, sex and histological differentiation (P>0.05). There was a positive correlation between the expression of EphA2 and VEGF (P<0.05). KaplanMeier survival analysis demonstrated that patients with high expression of EphA2 or VEGF had poorer overall survival compared with that in patients with relative low EphA2 or VEGF expression (P<0.05). Multivariate COX regression analysis revealed that both lymph node metastasis and EphA2 expression were independent prognostic factors for patients with LSCC. Conclusion Increased protein expression of EphA2 and VEGF in LSCC suggested that EphA2 and VEGF might play a critical role in the initiation and progression of LSCC.