Introduction: cyclooxygenase-2 (COX-2) is involved in pathogenesis of various tumors and possibly malignant skin tumors including malignant melanoma; however, there is not enough information about COX-2 expression in benign melanocytic lesions. In the present study we compared the expression levels of COX-2 in malignant melanoma and benign melanocytic lesions. Method: In this analytical study, 42 malignant melanoma from all 4 subtypes and 38 benign melanocytic lesions including dysplastic nevus, Spitz nevus and atypical nevus were evaluated for COX-2 expression using immunohistochemistry staining and intensity of cell staining (quantitatively and qualitatively). Results: Malignant melanoma compared to benign melanocytic lesions had significantly higher levels of staining (p<0.001), and much more intense coloration (p<0.001) and higher overall staining score (p<0.001). Regarding the COX2 staining between malignant melanoma subtypes, all four subtypes mostly had staining intensity over 60%. Also in terms of quality, the most intense staining was in the ALM ,and LM and NM had moderate staining intensity. With increasing depth of involvement, Cox2 staining increases. Intensity of cell staining was also higher in cases with tumor depth of 2-4 mm. Conclusion: The results indicates the effectiveness of COX2 in differentiating between malignant melanoma and benign melanocytic lesions. COX2 expression correlated with the depth of invasion. Although COX2 alone can not be used to differentiate melanoma from benign lesions, it can be helpful in combination with other methods,in determining the prognosis and future targeted therapies.