Context: A strong cause/effect relationship is evident between the expression levels of Cathepsin D (CD) in oral cancers and their local invasion and progression. Aims: The present study aims to assess the immunohistochemical expression of CD in normal oral mucosa, Verrucous Carcinoma (VC) and Oral Squamous Cell Carcinoma (OSCC). Settings and Design: A retrospective immunohistochemical study conducted in a tertiary care dental hospital with a sample size of 30. Materials and Methods: Immunohistochemical staining for CD was performed in 10 tissue sections each of normal mucosa, OSCC and VC. CD positivity, site of expression and intensity were analyzed semi-quantitatively under 10x and 40x magnification. Statistical Analysis Used: Cramer’s V test was done and p value is calculated. Results: CD expression was positive in 90% of normal oral mucosa. CD expression was mild in 33.3%, moderate in 33.3% and severe in 33.3% of well differentiated SCC, respectively. CD expression was mild in 25 %, moderate in 50% and severe in 25% cases of moderately differentiated SCC respectively. All cases of poorly differentiated SCC showed severe expression of CD. CD expression was positive in all cases of VC. Increased expression of CD correlated significantly with the presence of metastasis (p<0.03) and poor histologic malignancy grade (p < 0.05). Conclusion: CD was demonstrated in normal oral mucosa. There was a positive correlation between increasing grades of OSCC and increasing intensity of CD. It closely correlated with carcinoma invasion and progression. CD maybe a prognostic factor for SCC and may serve as a potential target for cancer therapy. More studies are needed to correlate CD expression in VC with its biologic behaviour. © 2023 Elsevier B.V., All rights reserved.