Meningiomas are one of the most frequent central nervous system tumors, with an annual incidence in the United States of approximately 2.5 per 100,000 people. An intense interest exists in evaluating new molecular markers that may serve as potential therapeutic targets. Cyclooxygenase-2 (COX-2) is upregulated in a number of epithelial tumors, but to date, there are no published reports about the expression of COX-2 in meningioma. This study evaluated a possible relationship between COX-2 expression and malignant progression of meningioma. Eighty-three specimens of meningioma from the surgical pathology database of Thomas Jefferson University Hospital were evaluated. The hematoxylin and eosin (H&E)-stained slides were reviewed, and representative paraffin-embedded tissue sections containing the index cases were chosen and immunohistochemically stained for COX-2 expression. The H&E-stained sections of the individual tumors were classified according to the 1993 and 2000 World Health Organization (WHO) criteria for grading of meningiomas. The COX-2-stained slides were then reviewed and an immunohistochemical score was calculated and analyzed for statistical significance. The association between tumor grade and COX-2 expression is highly significant using the WHO-1993 grading criteria, (p = 0.012). Tumors with a more aggressive phenotype (benign --> atypical --> malignant) are associated with increasingly higher levels of COX-2. Using the 2000 WHO classification system, however, the association between tumor classification and COX-2 expression was not significant (p = 0.17), although the overwhelming percentage of tumors expressed COX-2. The association of COX-2 and meningioma is unique and represents a potential area for therapeutic intervention with selective COX-2 inhibitors, either as adjunct or in combination with radiation therapy.