This study investigates the anti-cancer effects of licochalcone-E (Lico-E), a phenolic chalconoid derived from the genus Glycyrrhiza, in the human KB squamous cancer cell. Concentration-dependent cytotoxicity in KB cells increased following 24 hours of treatment with 12.5, 25, or 50 μg/ml Lico-E, with an estimated IC50 value of approximately 25 μg/ml. Chromatin condensation, a typical apoptotic phenomenon, was observed in KB cells treated with Lico-E. Consistent with this finding, Lico-E increased caspase-3 activity in KB cells. FasL, a death ligand associated with extrinsic apoptotic signaling pathways, was significantly up-regulated by Lico-E treatment. Subsequently, the pro-apoptotic factor caspase-8, a part of the extrinsic apoptotic signaling pathway, was activated in a concentrationdependent manner by Lico-E treatments. Expression of anti-apoptotic factors such as Bcl-2 and Bcl-xL, components of the mitochondriadependent apoptotic signaling pathway, significantly decreased following Lico-E treatment. Conversely, expression of pro-apoptotic factors such as Bax, Bad, Apaf-1, and caspase-9 increased with Lico-E concentrations. Finally, Lico-E activated caspase-3 and Poly (ADP-ribose) polymerase (PARP) to induce cell death. Z-VAD-fmk significantly inhibited cell death through suppression of caspase-3 expression in KB cells treated with Lico-E. Taken together, Lico-E induces KB cell death through death receptor and mitochondriadependent apoptotic signaling pathways.