Background: CyPPA is known as a positive modulator of SK2 and 3, which is found in HTS (high throughput screening for melanogenesis inhibitors). However, the effects of CyPPA on melanogenesis are not well known. Objectives: we evaluated CyPPA and impact on melanogenesis-related ERK signaling pathways. Methods: Mel-ab mouse melanocyte cells and human melanocytes were used to examine the effects of CyPPA on melanogenesis. To ascertain the CyPPA effect, microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase related protein (TRP) 1 and TRP 2 were examined by Western blotting and RT-PCR. We also investigated the phosphorylation of ERK, which is related to melanin regulation. Results: These results showed that melanin content and tyrosinase activity were significantly reduced in both cells without cytotoxicity. However, as it does not affect the activity of mushroom tyrosinase, CyPPA does not seem to be a direct inhibitor of tyrosinase. The level of MITF, Tyrosinase, TRP1 and TRP 2 expression were decreased. CyPPA induced phosphorylation of ERK and specific ERK phosphorylation inhibitor, PD98059, partially recovered the CyPPA-mediated inhibition of proteins associated with melanin synthesis such as MITF, TRP1, and TRP2. Conclusion: These results suggest that CyPPA inhibits melanogenesis through activation of the ERK signaling pathway.