Eph-ephrin binding has been linked to tumor biology and VEGF has been reported to participate in the tumor angiogenesis regulated by Eph-ephrin. The present study was designed to evaluate the expression of EphA2 and VEGF in relation to angiogenesis and clinical outcome in squamous cell carcinoma of oral tongue. Immunohistochemical staining was used to determine the protein expression levels of EphA2 and VEGF in 59 surgically resected tongue carcinomas and 10 tumor-free mucosas. In all cases, microvessel density (MVD) was evaluated by counting CD34-reactive endothelial cells or endothelial cell clusters. Both EphA2 and VEGF staining activities in squamous cell carcinoma of oral tongue were more significant than those in normal mucosa (P<0.01). MVD had significant correlations with EphA2 and VEGF expression (P<0.01). The EphA2, VEGF, and MVD were significantly correlated with tumor size, clinical stage, lymph invasion, recurrence, and distant metastasis (P<0.05). Multivariate analysis showed EphA2, VEGF expression, MVD, and clinical stage had an independent prognostic effect on overall survival. We conclude that the overexpression of EphA2 and VEGF are related to malignancy in squamous cell carcinoma of oral tongue. Clinical outcomes raised the possibility that the overexpression of those proteins might contribute to tumor angiogenesis and have prognostic value in tongue cancer.