Sciellin, a precursor of the cornified envelope, contains a LIM domain that is known to function as a protein interaction module. In this study we used the yeast two-hybrid system to find proteins interacting with sciellin and identified vitamin D-upregulated protein 1 (VDUP1). This protein had not been reported in skin, but was shown in a number of cells to interact with reduced thioredoxin and regulate its function. Using an affinity VDUP1 column and an extract of cultured keratinocytes it was shown that VDUP1 and sciellin interacted. By immunohistochemistry VDUP1 was localized to the basal layer of normal human epidermis and the inner and outer root sheaths but not the matrix of the hair follicle. In the proliferative epidermis of psoriasis, VDUP1 was most highly expressed in the upper epidermal layers. In cultured keratinocytes, VDUP1 and sciellin were more highly expressed in cells undergoing differentiation. Colocalization of the proteins could be demonstrated by immunohistochemistry in parts of the follicle, psoriatic epidermis, and cultured keratinocytes. Our results suggested that VDUP1 could have a unique role in epidermis regulating the conversion of postmitotic cells to differentiating ones.