Cyclooxygenase-2 (COX-2) is involved in the development and progression of many tumors, and its inhibition has been shown to block tumor growth. This study examined COX-2 expression in primary and metastatic Merkel cell carcinoma (MCC). Formalin-fixed paraffin-embedded tissues from 26 primary MCCs and 7 lymph node metastases were stained immunohistochemically with a monoclonal antibody directed against COX-2, and the percentage and intensity of staining were analyzed semiquantitatively. Immunopositivity for COX-2 was found in 20 primary tumors (77%), and was diffuse in 16 of them (80%). Staining intensity was strong in 5 tumors (19%), moderate in 6 (23%), and weak in 9 (35%). Five metastases (71%) showed similar staining. Prominent mitotic activity was associated with more diffuse COX-2 immunopositivity. No association was found between COX-2 expression and outcome. This study confirms that most MCCs express COX-2 and shows that COX-2 expression is related to one parameter of aggressive behavior--a high mitotic rate--but not to any others. The possibility of treating MCC with COX-2 inhibitors should be considered.