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Several studies illustrated considerably elevated levels of cyclooxygenase-2 (COX-2) protein in various types of human cancer including malignant melanoma. Recently, it was reported that COX-2 is strongly expressed in malignant melanoma and may be correlated with the development and progression of disease. In contrast, other groups did not detect COX-2 protein in primary melanoma cells but did in infiltrating inflammatory cells or metastases. However, there are no reports about patterns or alterations of COX-2 expression in melanoma cells during disease progression or of a correlation between COX-2 expression and overall survival. The aim of this study was to investigate whether there is a correlation between expression of COX-2 protein and disease prognosis in malignant melanoma. We therefore analyzed the expression of COX-2 protein by immunohistochemistry in 101 primary malignant melanomas and 28 metastases and correlated our data with Breslow tumor thickness, Clark levels, different melanoma subtypes, metastases, and overall survival. We detected a strong COX-2 expression in 95% of all primary melanomas, primarily restricted to melanoma cells as shown by various immunohistochemical methods. Levels of COX-2 expression in primary melanoma and corresponding metastases remained stable. A significant correlation between immunohistochemical staining intensity and tumor thickness was demonstrated. Furthermore, Kaplan–Meier curves illustrated a significant correlation between staining intensity and disease-specific survival. Our findings emphasize that the COX-2 protein might be a novel prognostic marker. Owing to its strong expression in melanoma cells it might also be a reasonable therapeutic target.