The aim of the present work was to clarify the anti-melanogenic mechanism of non-steroidal anti-inflammatory drugs (NSAIDs). Mefenamic acid, diclofenac, and nimesulide were used in this study, and these drugs inhibit melanin synthesis in B16F1 melanoma cells. To elucidate the anti-melanogenic mechanism of NSAIDs, we performed western blotting analysis for melanogenic proteins, such as tyrosinase, TRP-1, and TRP-2. All NSAIDs used in this study inhibited tyrosinase protein level. Semi-quantitative RT-PCR analysis showed that the depigmentation effect of mefenamic acid and nimesulide might be due to the inhibition of tyrosinase gene transcription. These results indicate that NSAIDs inhibit α-MSH-enhanced melanin synthesis, and are candidate anti-melanogenic agents since they might be effective in hyperpigmentation disorders.