p63, a member of the p53 family, is transcribed from two different promoters giving rise to two different proteins: TAp63 that contains the N-terminal transactivation domain and DeltaN that lacks this domain. In this article we describe a new target gene Scotin induced by TAp63 during epithelial differentiation. This gene was previously isolated as a p53-inducible proapoptotic gene and the protein is located in the endoplasmic reticulum and in the nuclear membrane. Scotin expression is induced in response to endoplasmic reticulum (ER) stress in a p53 dependent or independent manner. We detected Scotin upregulation in primary keratinocyte cell lines committed to differentiate. In this paper we also show that Scotin is expressed in the supra basal layer of the epidermis in parallel with TAp63, but not DeltaNp63 expression. We conclude that Scotin is a new p63 target gene induced during epithelial differentiation, a complex process that also involves ER stress induction.