Zinc-alpha 2-glycoprotein (Zn alpha 2gp) is almost ubiquitous in body fluids. We have found it to be also present in stratified epithelia. We compare its mRNA expression in cells from human epidermis and buccal mucosa cultured in media of graded differentiation potential (attained by varying calcium ion concentration and adding serum). The Zn alpha 2gp gene is upregulated in both epithelia with differentiation and further with exposure to interferon gamma or transforming growth factor beta 1. The upregulation by these agents increases with differentiation in epidermal cells, but peaks in the low-differentiation medium in buccal epithelia. We compared gene expression levels of Zn alpha 2gp with those of characteristic cytokeratins of stratified epithelia (k5 for basal cells, K10 for epidermal suprabasal cells, and K13 for mucosal suprabasal cells). This pattern correlation associates Zn alpha 2gp cell-type dependently with late differentiation, i.e. with keratin K10 in epidermis and with K13 in buccal epithelium.