Artemisia capillaris has been used in traditional Korean medicine for its variety of pharmacological activities. Previous studies have suggested that the essential oil of A. capillaris has chemopreventive potential, even though the mechanism of its action is unclear. This study examined whether or not the essential oil isolated from A. capillaris induces apoptosis in the human oral epidermoid carcinoma cells along with the possible mechanism(s) of the essential oil-mediated cytotoxicity. The essential oil induced cell death of KB cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of condensed and/or fragmented nuclei, and the generation of a cleaved PARP product. Treating the cells with the oil also caused changes in the mitochondrial level of the Bcl-2 family proteins such as Bcl-2 and Bax, thereby inducing the release of cytochrome c into the cytosol. Additional experiments using caspase or mitogen-activated protein kinase inhibitors suggested the involvement of the p38/NF-kappaB and JNK/Bcl-2-mediated pathways as well as caspase activation in the oil-mediated apoptosis. Collectively, we believe that the essential oil of A. capillaris induces apoptosis in human oral cancer cells and that it might be a good resource for searching new drugs, especially anticancer drugs.