Abstract Squamous cell carcinomas (SCC) were experimentally produced in hairless mouse skin, and cysteine protease and its inhibitor were simultaneously purified from extracts of 1 g of tissue of SCC and normal skin. Activity of cysteine proteinases, M r > 50,000 and M r 28,000, increased in SCC compared to those in normal skin. SCC also showed elevation of cysteine proteinase inhibitor activity and M r 13,000 and M r 82,000 inhibitors were purified. M r 13,000 inhibitor was found to have biochemical properties which were the same as those of the inhibitor present in normal skin. M r 82,000 inhibitor was not detectable in normal skin and it differed from a serum inhibitor with a similar M r in terms of activity and stability at acidic pH. The findings suggest that the increased activity of both cysteine proteases and endogenous inhibitors may be involved in the regulatory mechanisms of malignant cell metabolism and tissue remodeling associated with SCC development.