We have previously described the properties of desquamin, a cell adhesion molecule in the stratum corneum with lectin-like properties specific for amino sugars. We report here that desquamin is also a trypsin-like serine proteinase. It degrades several chromogenic peptides with arginine in the P1 position, with greatest activity for the tissue plasminogen activator peptide; it has no chymotrypsin-like activity. The enzymatic activity of desquamin is inhibited by aprotinin, leupeptin, and soybean trypsin inhibitor. The Km for all active substrates is in the millimole range and the pH for optimal activity is near 10. The enzymatic activity is stable in the temperature range from 37 to 80 degrees C, peaking near the upper end; it is only partially inhibited at 100 degrees C. Using zymogels with immobilized substrates, we show that desquamin degrades both casein and human keratins. Because desquamin is localized to the lipid envelopes of the stratum corneum and can function as an enzyme (and is extremely resistant to chemical and thermal degradation), it is in a position to play a crucial role in desquamation.