We report here the complete nucleotide sequence of a gene encoding the 50-kDa keratin expressed in abundance in human epidermal cells. According to its sequence, this gene has a single transcriptional initiation site and a single polyadenylylation signal. Nuclease S1 mapping of this gene with total human epidermal mRNA confirmed the presence of a single initiation site for the 50-kDa keratin gene. When the regulatory sequences 5' upstream from this gene were examined, three sequences that share significant homology with viral and immunoglobulin enhancer elements were found. In comparison, the sequence of the regulatory region of vimentin, a structurally similar intermediate filament gene, was highly divergent [Quax, W., Egberts, W. V., Hendriks, W., Quax-Jeuken, Y. & Bloemendal, H. (1983) Cell 35, 215-223]. This finding may provide a clue to understanding the molecular mechanisms underlying the widely varying levels of expression of different intermediate filament genes in different tissues.