Background: Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. Methods: COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. Results: All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. Conclusion: COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity.