Tocotrienols are known to possess potent antioxidant, anticancer, and cholesterol lowering activities. Being able to rapidly penetrate the skin, these vitamin E isoforms have been explored for potential treatment against melanoma. This study aimed to elucidate the mechanism involved in the anti-melanogenic effects of delta-tocotrienol (delta T3) in B16 melanoma cells. Results showed that at 20 mu M of delta T3 significantly inhibited melanin formation and ROS generation. Treatment with delta T3 also effectively suppressed the expression of melanogenesis-related proteins, including MC1R, MITF, TYRP-1, and TYRP-2. More importantly, we observed that the mitogen-activated protein kinase (MAPK) pathway was involved in mediating delta T3's inhibitory effect against melanin production. Specifically, delta T3 treatment markedly induced the activation of extracellular signal-regulated kinases (ERR). The use of ERR activation inhibitor (PD98059) abrogated the delta T3-mediated downregulation expression melanogenesis-related proteins and restored melanin production. Furthermore, siRNA targeting ERK effectively blocked the delta T3-induced repression of tyrosinase and TYRP-1 expression. These results suggest that delta T3's inhibitory effect against melanogenesis is mediated by the activation of ERR signaling, thereby resulting in downstream repression of melanogenesis-related proteins and the subsequent melanin production. These data provide insight to delta T3's effect and the targeting of ERR signaling for treatment against melanogenesis. (C) 2014 Published by Elsevier GmbH.