Purpose: Tumor associated angiogenesis and/or lymphangiogenesis are known to be linked by VEGFR signaling pathways. These processes are regulated by several growth factors including VEGFR-2, VEGFR-3. E7080 is an orally active inhibitor of multiple tyrosine kinases including VEGFR-2, 3. Therefore, it was proposed that E7080 may inhibit angiogenesis and lymphangiogenesis. The aim of this study was to determine the effect of E7080 in a nude mouse model of OSCC. Methods: KB cells were xenografted into the submucosal tissue of the mouth floor of athymic mice. Seven days after the xenograft, the mice were randomized into 2 groups. E7080 were administered orally to the experimental group once per day. The mice were sacrificed 3 weeks after the treatment. The tumors were examined histopathologically. Immunohistochemical assays with anti- VEGF-C, VEGFR-2, VEGFR-3, phosphorylated VEGFR-2/3 (pVEGFR-2/3), and D2-40 antibodies were then performed. Results: The transplantation of human OSCC tumor cells into the mouth floor resulted in the formation of orthotopic tumors. The experimental (E7080 treatment) group showed a slowly increased tumor volume. Moreover, immunohistochemical staining demonstrated higher levels of VEGF-C, VEGFR-2, VEGFR-3, pVEGFR-2/3 and D2-40 expression in the control group than in the experimental group. Conclusion: These results suggest that E7080 may provide therapeutic benefits in OSCC.