Background: IFN-γ has been identified as an inflammatory cytokine involved in various skin disease including psoriasis and chronic phase of atopic dermatitis or UVB irradiation. Objectives: In this study, the effects of IFN-γ on melanogenesis were investigated. Methods: Melanin content and tyrosinase activity assay were performed. A real-time PCR and western blot analysis were conducted to investigate the effect of IFN-γ on tyrosinase and MITF. To determine IFN-γ affects the MITF binding to the tyrosinase promoter and CREB binding to the MITF promoter, we used EMSA. A PLA was used to determine whether STAT1 inhibits the association CBP and CREB by binding to CBP. Results: IFN-γ inhibits basal and α-MSH-induced melanogenesis in B16 melanoma cells and in normal human melanocytes. MITF mRNA and protein expressions were significantly inhibited in response to IFN-γ. IFN-γ inhibited CREB binding to the MITF promoter but did not affect CREB phosphorylation. Instead, IFN-γ inhibited the association of CBP and CREB through the increased association between CREB binding protein (CBP) and STAT1. These findings suggest that IFN-γ inhibits both basal and α-MSH-induced melanogenesis by inhibiting MITF expression. The inhibitory action of IFN-γ in α-MSH-induced melanogenesis is likely to be associated with the sequestration of CBP via the association between CBP and STAT1. Conclusion: These results suggest that IFN-γ plays a role in controlling inflammation- or UV-induced pigmentary changes.