The hypo-pigmentation of human skin on the palms and the soles compared with other areas of the body has recently been reported to be due to mesenchymal–epithelial interactions via a fibroblast-derived factor, dickkopf 1, an inhibitor of the canonical Wnt signaling pathway. Recently, it has been reported that keratinocytes play a significant role in skin color determination by producing cytokines involved in melanogenesis. Thus, we hypothesized that the downregulated expression of keratinocyte- or fibroblast-derived melanogenic cytokines may also be responsible for the decreased function of palmoplantar (PP) melanocytes in addition to the suppressive effects of dickkopf 1 on melanogenic function in epidermal melanocytes. Immunohistochemistry revealed that the number of tyrosinase, S100α, c-KIT, endothelin B receptor (ETBR), SOX10, and microphthalmia-associated transcription factor (MITF) immuno-positive melanocytes is significantly reduced in PP epidermis. In contrast, dopa-histochemistry demonstrated no substantial reduction in melanocyte populations in PP epidermis. Real-time RT-PCR revealed that the expression of stem cell factor (SCF) and endothelin (ET)-1 mRNAs in PP skin was significantly downregulated. In parallel, immunohistochemistry revealed that SCF and ET-1 immuno-staining was markedly attenuated in PP skin. Western blotting revealed that the expression of SCF, c-KIT, and MITF-M proteins was significantly decreased in PP skin. These findings suggest the possibility that downregulation of ET-1/SCF/receptor linkages is also associated with the decreased function of melanocytes in PP skin.