In this study, we found that oral squamous cell carcinomas (OSCCs) in Korean patients have a high level of COX-2 expression when compared with normal mucosa. Sulforaphane (SFN), rich in cruciferous vegetables, has been reported to display anti-cancer activity against many cancers. However, the effect and molecular mechanism of SFN in the proliferation of OSCC still remains unclear. To elucidate this mechanism, we investigated the anti-proliferative effect of SFN on KB and YD-10B cells and demonstrated that SFN significantly induced caspase-dependent apoptosis. Also, we observed that SFN inhibited COX-2 but not COX-1. In addition, bcl-2 protein, one of downstream targets of COX-2, was down-regulated by SFN. Furthermore, SFN also inhibited tumor growth in KB cell xenografts. These results show that SFN can act as a potent anti-oral cancer compound by inhibiting COX-2 activity.