SUMMARY After 14 weeks of topical application of 0.1% all-trans -retinoic acid to the napes of volunteers, we observed a 2.5-fold increase in the thickness of epidermis, owing to an increase ( p Ͻ 0.001) in the number and size of keratinocytes and the induction of keratin 6. These changes in the differentiation of epidermal keratinocytes were paralleled by an increase in the amount of Cx43, a connexin that is normally expressed in human epidermis, and by the massive induction of Cx26, which is barely detectable in normal interfollicular epidermis, as judged at both the transcript (Northern blotting) and the protein level (immunolabeling). In contrast, retinoic acid treatment did not alter the morphology and connexin pattern of hair follicles or of sebaceous and sweat glands, and did not induce the expression of other connexins (C32, Cx37, Cx40) in either skin adnexae or epidermis. These observations suggest that the expression of two distinct connexins by interfollicular keratinocytes is related to selective changes in the differentiation program of epidermis that are induced by retinoic acid.