Topical all-trans retinoic acid (RA) produces a number of epidermal changes which are indistinguishable from those observed following treatment with a local irritant, namely sodium lauryl sulphate (SLS). This observation has led to criticism that the efficacy of RA in disorders such as photoageing, is merely a result of irritancy. In stratified epithelia, the cellular differentiation process is characterized by a stepwise synthesis of cell surface carbohydrates, and each type of stratified epithelium has its own specific pattern of carbohydrate expression. Glycosyltransferases, which are responsible for carbohydrate synthesis, are influenced by retinoids. Thus, we investigated whether epidermal cell surface glycosylation is altered in skin treated with topical RA, and contrasted it with changes induced by topical SLS. Skin biopsies were obtained from seven normal volunteers who had been treated, on three separate areas of buttock skin, with single applications of 0.1% RA, 2% SLS, or vehicle creams, followed by 4-day occlusion. Biopsies were assessed immunohistologically using highly specific monoclonal antibodies to cell surface carbohydrates (types 1, 2 and 3 chain structures), previously demonstrated in the epidermis and in oral mucosal epithelium. Although type 1 chain structures were not demonstrated in any of the samples, the distribution of type 2 and 3 chain structures in RA-treated epidermis was altered towards that seen in a mucosal epithelium. T antigen, a mucin-type cell surface carbohydrate structure normally expressed throughout the epidermis, was only observed in the granular layer of RA-treated epidermis--a feature of mucosal epithelia. Ley, normally only seen in non-keratinized buccal epithelium, was strongly expressed in RA-treated epidermis. In contrast, the glycosylation pattern of the SLS-treated epidermis was not significantly different from that observed after vehicle treatment. Thus, RA treatment converts normal stratified epithelium towards the phenotype of mucosal epithelium with a decrease in T antigen and a concomitant increase in Ley. These changes are not observed following treatment with SLS and identify an important difference between RA effects and irritancy.