The human calcium-binding protein (hS100A15) was first identified in inflamed hyperplastic psoriatic skin, where the S100A15 gene is transcribed into two mRNA splice variants, hS100A15-S and hS100A15-L. To compare the contribution of the human S100A15 (hS100A15) isoforms in skin inflammation and differentiation, we determined the expression, distribution and regulation of hS100A15-S and hS100A15-L in psoriasis and chronic atopic eczema compared with normal skin. We found that both hS100A15 transcripts were mainly distributed in the epidermis of normal and inflamed skin with hS100A15-L being the predominantly expressed mRNA isoform in both psoriasis and atopic eczema. In cultured keratinocytes, IL-1beta and Th1 cytokines significantly induced hS100A15-L compared with hS100A15-S. In contrast, Th2-derived cytokines had no influence on the expression of either hS100A15 splice variant. Differentiation of human keratinocytes induced by 1.2 mm calcium resulted in the upregulation of both hS100A15 mRNA isoforms. Our data show that both hS100A15 splice variants are differentially regulated and expressed with epidermal differentiation and skin inflammation. Overexpression of hS100A15 in chronic inflammatory skin diseases and regulation by inflammatory cytokines and calcium suggest that hS100A15 is involved in Th1-associated epithelial responses and epidermal maturation in normal and diseased human skin.