The incidence of oral cancer is high in certain parts of the world including Southeast Asia. Smokeless tobacco and areca nut chewing is proposed as a possible factor. Cyclooxygenase 2 (COX-2) receptors are present on neoplastic cells and are proposed to participate in initiation, transformation, progression and metastasis of cancer. In a prospective case-controlled study, 42 cases of squamous cell carcinoma of the oral cavity, 13 cases of oral premalignant lesions, and oral mucosa from 32 normal subjects were evaluated for COX-2 gene expression using reverse transcriptase polymerase chain reaction. The mean age of the patients with oral cancer was 60.2 years. The majority of cancer patients were males while the majority of controls were females. A significantly higher expression of COX-2 was found in cancer patients compared to both normal controls (p=0.0001) and patients with premalignant lesions (0.015). The expression in premalignant lesions was higher compared to healthy subjects (p=0.05). COX-2 expression in oral cancer was found to be independent of grade of tumor and stage of disease. These results show up-regulation of the COX-2 gene in oral cancer and precancer. This suggests a role for COX2 receptors in oral cancer carcinogenesis, and provides the foundation for a large randomized trial to determine the role COX2 inhibitors may play in prevention of oral carcinogenesis.