Epidemiological studies have shown a lower incidence of breast, prostate, and colon cancers in Asian countries, particularly China and Japan, than in the United States. It is believed that genistein, a natural tyrosine kinase inhibitor and a metabolite of soy products, may be responsible for the protection from these cancers. Genistein was shown to inhibit cell proliferation and to induce cell cycle arrest at the G2-M phase in breast, prostate, and jurkat T cell leukemia cell lines. However, such studies have not been reported in squamous cell cancers of the head and neck. In this report, we show that genistein inhibits proliferation of a squamous cell carcinoma cell line HN4. Additionally, genistein caused cell cycle arrest at the S/G2-M phase and induced programmed cell death (apoptosis) in these cells. These effects appear to be dose and time dependent, irreversible, persisting when the cells were recultured in genistein-free medium for up to 72 hours, and specific for tumor cells, because genistein did not affect normal keratinocytes. These results suggest that if genistein shows similar results in clinical trials, it can be a potential chemopreventive/chemotherapeutic agent for cancers of the head and neck.