Okadaic acid is a C₃₈ fatty acid derivative that is known to specifically inhibit the activity of protein phosphatase 2A (PP2A). Previously, we reported that inhibition of PP2A by okadaic acid elicited extracellular signal-regulated kinase (ERK) activation, and that PP2A may be involved in melanogenesis. However, the effects of okadaic acid on melanogenesis have not been completely evaluated. In the present study, we investigated the molecular mechanisms involved in okadaic acid modulation of melanin synthesis in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab. Treatment with okadaic acid inhibited melanin production in a dose-dependent manner. Moreover, okadaic acid led to a decrease in tyrosinase protein levels without altering mRNA expression. Therefore, we investigated whether the decreased level of tyrosinase by okadaic acid was related to proteasomal degradation of tyrosinase. We found that MG132, a proteasome inhibitor, almost completely abolished both the downregulation of tyrosinase levels and the inhibition of melanin synthesis by okadaic acid. Taken together, our data indicate that okadaic acid inhibits melanin synthesis via proteasomal degradation of tyrosinase.