Background: Cathepsin-D, a protease, which is an invasion promoter and plays a central role in solid tumors including oral cancer. Our aim of the study was to look for their expression pattern in epithelium and stroma of odontogenic cysts and tumors and correlate their aggressiveness to the staining intensity. Materials and Methods:To elucidate the expression patterns of this marker, we examined immunohistochemically on formalin-fixed, paraffin-embedded sections of 24 odontogenic cysts and 10 odonogenic tumors, which are received for histopathologic examination in the Department of Oral Pathology, The Oxford Dental College and Hospital, Bengaluru. Results:The epithelium of granular cell ameloblastoma (GCA) and odontogenic keratocyst (OKC) showed maximum staining with spillage of stained material in the connective tissue wall and at the separation of epithelium to capsule in OKC compared to other cysts and tumors. Conclusions: Cathepsin-D could be one of the enzymes important in separation of epithelium and connective tissue in OKC which helps in recurrence and intense expression in GCA with spillage into stroma, compared to other odontogenic tumors may explain its aggressive behavior, recurrence, and metastatic potential. To further validate our findings, it is suggested to use more sample size and monoclonal antibody for cathepsin-D.