BACKGROUND: Melanoma continues to be a therapeutic challenge for the medical community owing to the scarcity of effective agents available to treat the disease. Honokiol, a traditional Chinese herb, has been proven to have anti-cancer effects in various cell types, therefore we hypothesized it may have similar cytotoxic capabilities against melanoma cells in vitro. METHODS: Two cell lines, SK-MEL2 and MeWo, were grown in culture and exposed to increasing doses of Honokiol. Cell proliferation, cytochrome c release into the cytosol, intra-cellular caspase activity, and mitochondrial depolarization were then evaluated after treatment with honokiol. RESULTS: Melanoma cells in culture underwent cell death, had increased cytosolic cytochrome c, showed greater caspase activity, and demonstrated increased mitochondrial depolarization after treatment when compared to controls. CONCLUSIONS: It appears that honokiol is an effective inhibitor of cultured human melanoma cells. J. Surg. Oncol. 2011; 104:260–264. © 2011 Wiley-Liss, Inc.