Objectives: The purpose of this study was to evaluate the antiangiogenic effects of genistein on the tumor growth, angiogenesis and in vitro invasion in an oral squamous cell carcinoma model. Methods: Northern blot analysis for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), in vitro invasion assay and gelatin zymography were carried out for HSC-3 cells treated with genistein. After injecting genistein into nude mouse(balb/c/nu), tumor growth rate and metastasis to lymph node were compared. The microvessel density (CD31) was subsequently analyzed by immunohistochemistry. Results: The genistein treated group showed a down-regulation in VEGF mRNA expression, but not in bFGF mRNA expression. Genistein reduced in vitro invasion through the artificial basement membrane and gelatin zymography also showed a reduced gelatinolytic activity in the genistein-treated group. In the genistein-treated mice, a significantly lower CD31 immunoreactivity was found. Conclusions: These results suggest the possible use of genistein as an anti-cancer agent in oral squamous cell carcinoma. However, research is recommended to confirm that genistein may be employed as an adjunct treatment modality for OSCC..