We have observed that lipopolysaccharide (LPS) induces pigmentation in melanocytes and in this study have examined whether these responses are mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. LPS appears to stimulate the pigmentation of melanocytes and cultured skin. LPS was found to induce the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase protein in cells. Stimulation of melanocytes with LPS led to time dependent phosphorylation of p38 MAPK. Furthermore, p38 MAPK functionally regulated the LPS-induced melanin formation in melanocytes; a p38 MAPK inhibitor, SB203580, almost completely attenuated the LPS-mediated up-regulation of melanin synthesis and induction of MITF and tyrosinase expression. These findings indicate that activation of p38 MAPK plays an important role in LPS-induced melanogenesis by up-regulating MITF and tyrosinase expression.