Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers. OSCC generally has a poor prognosis due to its tendency towards local invasion and subsequent metastasis, which is mediated by multiple proteolytic enzymes and angiogenesis. The purpose of this study was to evaluate the anti-cancer effects of genistein, a soybean product known to be an effective natural anti-angiogenic agent, with respect to tumor growth, angiogenesis and in vitro invasion in an OSCC model. Northern blot analysis for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase-2 (MMP-2), in vitro invasion assay and gelatin zymography were carried out for HSC-3 cells treated with genistein (27.3 microg/ml). In the animal experiment, genistein (0.5 mg/kg) was injected into tumor (HSC-3)-bearing mice (male balb/c/nu). The tumor growth rate and metastasis to lymph node or lung were compared and the microvessel density (CD31) was subsequently analyzed by immunohistochemistry. The genistein-treated group showed a down-regulation in VEGF mRNA expression, but not in bFGF and MMP-2 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. However, the tumor growth and metastatic behavior in the experimental group and the control group were similar and there were no significant differences. These results suggest the possible use of genistein as an anti-cancer agent in oral squamous cell carcinoma. However, it appears from the present study that anti-angiogenic therapy consisting of a single application of genistein may not provide a satisfactory treatment for OSCC. As a result, further research is recommended to confirm that genistein may be employed as an adjunct treatment modality for OSCC.