We investigated the effects of ML106 on melanogenesis in B16F10 melanoma cells. Our results showed that ML106 decreased melanin content and tyrosinase activity in a dose-dependent manner. Interestingly, ML106 did not inhibit microphthalmia-associated transcription factor (MITF) expression, but did decrease tyrosinase expression. Thus, we further investigated the expression and degradation of tyrosinase and related signal transduction pathways. Although ML106 increased glycogen synthase kinase 3beta (GSK3beta) activation, the level of beta-catenin level was not affected. Thus, we excluded the involvement of GSK3beta and beta-catenin in ML106-induced hypopigmentation. However, ML106 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK), causing down-regulation of tyrosinase. Thus, we next investigated whether tyrosinase down-regulation was due to proteasomal degradation by p38 MAPK activation. We found that ML106-induced tyrosinase down-regulation was restored by MG132, a proteasome inhibitor. Thus, we propose that ML106 has hypopigmentary activity through tyrosinase degradation via p38 MAPK phosphorylation.