Terrestrial vertebrates, particularly eutherian species, show highly stratified epithelium. Recent evidence has indicated that the special organization of the stratification depends largely upon a variety of adhesion molecules, and therefore probably upon some proteases and their inhibitors. The present paper shows the expression of squamous cell carcinoma antigen (SCC antigen), a new serine protease inhibitor, in the integuments of various vertebrate species. In Southern blot analysis, SCC antigen gene was detected in human, monkey, dog, cat, horse, cow, goat, and rabbit, but not in wallaby, chicken, tortoise, frog, or carp. Immunohistochemical studies with the monoclonal antibody against SCC antigen revealed that this protein is present at the intermediate layer of the human squamous epithelium but not at the parabasal layer. SCC antigen is also absent at the epithelial region adjacent to the squamo-columnar junction where the stratification is not fully organized yet. These results indicate that SCC antigen may play an important role in the regulation of the stratification of squamous epithelium.