The early growth response gene, Egr-1 (NGFI-A, krox 24, zif 268, TIS 8), is a member of a family of genes with suggested importance in the regulation of cell growth and differentiation. Retinoic acid has been shown to markedly induce Egr-1 gene expression in mouse embryonal carcinoma cells and rat preosteoblastic cells. In this study we demonstrate that treatment of cultured human skin fibroblasts with retinoic acid results in a rapid transient four-fold induction of Egr-1 transcripts, being maximum at 60 min and returning to a basal level by 120 min. However, treatment of cultured human keratinocytes with retinoic acid did not significantly induce Egr-1 transcripts. Expression of Egr-1 message in keratinocytes was observed to be induced by fetal bovine serum and tetra-decanoyl phorbol acetate, whereas calcium, 1,25-dihydroxyvitamin D3, and cyclic adenosine monophosphate caused little or no induction. Topical application of 0.1% retinoic acid cream in vivo resulted in a two- to threefold induction of Egr-1 transcripts following treatment for 24 and 48 h, returning to nearly basal levels by 96 h. Taken together, these data are consistent with the possibility that Egr-1 is a proximal component of an intracellular molecular cascade that may give rise to alterations in cell phenotype in response to retinoic acid.