Inflammatory cytokines are closely related to melanogenesis in melanocytes. Here, I studied whether IFN-γ affects melanogenesis, and if so, what is the underlying mechanism involved in it. Using B16 melanoma cell lines and primary human melanocytes, I demonstrated that alpha-MSH induced tyrosinase expression and activity and TRP-1, TRP-2 expression were suppressed by IFN-γ, which resulted from the inhibition of MITF expression, upstream molecule of tyrosinase. Moreover, the inhibitory effects on MITF expression by IFN-γ occured through the disturbance of CREB binding ability on MITF promoter by reducing the binding of CBP and CREB. These results suggest that IFN-γ decreases melanogenesis through inhibiting the binding of CBP and CREB and block the MITF and tyrosinase expression.