Interferon (IFN)-gamma has been implicated in the pathogenesis of several autoimmune disorders and inflammatory skin diseases. To identify novel mediators involved in the IFN-gamma response we have used differential hybridization of a cDNA library prepared from IFN-gamma-treated HeLa cells to isolate a gene that is induced following treatment with IFN-gamma. We report here the molecular cloning and characterization of a cDNA detecting a 1.6-kb mRNA that accumulated in response to IFN-gamma but not in response to IFN-alpha or IFN-beta. The gene is regulated by IFN-gamma in human cell lines of epithelial origin. The mRNA encodes a predicted protein of 432 amino acids and the primary structure of the protein demonstrates that it is a novel member of developmentally regulated keratin class I genes.