Growing evidence has shown that cyclooxygenase-2 (COX-2), an enzyme capable of catalyzing prostaglandin production, plays a key role in carcinogenesis. Selective COX-2 inhibitors have been shown to reduce the establishment of tumors such as oral squamous cell carcinoma (OSCC) and premalignant conditions such oral submucous fibrosis (OSMF) in experimental models. The aim of this study was to investigate the immunohistochemical expression of COX-2 in OSCC and OSMF with the normal oral mucosa as control. Forty-five formalin-fixed paraffin-embedded samples comprising 20 OSCC, 20 OSMF, and 5 normal oral mucosa specimens were withdrawn from the archives of the Department of Oral and Maxillofacial Pathology for immunohistochemical examination for COX-2 expression. Negative and less than 5% COX-2 positivity was considered negative expressions, while greater than or equal to 5% COX-2 positivity was considered positive expression. The data obtained were statistically analyzed. The difference in percentages of expression in normal mucosa, OSCC, and OSMF was highly significant (P < 0.01). In comparison to normal mucosa, OSCC and OSMF had an increased level of COX-2 expression. However, there was an insignificant difference between the various histological gradings of OSCC and OSMF. The results of the present study confirm the role of COX-2 in carcinogenesis and in the progression of premalignant conditions to malignancy.