Cyclosporin A (CsA) has been shown to inhibit, in vitro, the proliferation of cultured normal and neoplastic keratinocytes and to exert also in vivo an antiproliferative effect on keratinocytes of normal human skin xenografted onto nude mice. To gain further insight into the effects of CsA on human skin we investigated the immunohistochemical expression of several epidermal proliferation- and differentiation-associated antigens in the same model: six-week-old nude mice received a xenograft of full-thickness normal human skin; six animals subsequently received a daily subcutaneous injection of 50 mg/kg of CsA diluted in olive-oil while the others received an equivalent volume of olive-oil. The rate of epidermal proliferation was evaluated through a BrdU pulse-labelling technique, and was found to be decreased by 56% in the CsA-treated epidermal xenografts as compared to the controls. The xenografts were further examined for the expression of the following antigens: Epidermal Growth Factor- and Transferrin-receptors, Ki-67, 56.5 kD keratin polypeptide, Filaggrin, Involucrin, beta 2-microglobulin, Ulex Europaeus I- and Peanut-Agglutinin-binding sites. Most of these antigens were unchanged on CsA-treated human xenografts. However, the 56.5 kD keratin polypeptide which was consistently expressed by both basal and suprabasal epidermal keratinocytes in control xenografts showed a normal expression pattern (i.e. suprabasal keratinocytes only) in three out of the six CsA-treated xenografts. These results raise the possibility that, concurrently with a cytostatic effect, CsA may also affect keratinocyte differentiation and that this effect, possibly contributes in the beneficial effect of CsA in diseases of abnormal keratinization.