Malignant mesothelioma (MM) is a fatal tumor of increasing incidence, which is resistant to current therapy. Cyclooxygenase-2 (COX-2) plays an important role in solid tumor growth, invasiveness, and angiogenesis, in part through the synthesis of prostaglandins such as prostaglandin E(2) (PGE(2)). In a prospective study, we evaluated COX-2 expression in snap-frozen, surgically resected MM tissue specimens using immunohistochemistry and semiquantitative Western blotting. PGE(2) was assessed by enzyme immunoassay. Thirty epithelioid, 10 biphasic, and 8 sarcomatoid tumors were evaluated. Immunohistochemistry demonstrated strong cytoplasmic tumor cell and variable stromal staining in all of the cases. COX-2 protein levels were correlated with clinicopathological prognostic factors using Kaplan-Meier and Cox proportional hazards models. High COX-2 band densitometry values correlated with poor survival (P = 0.008). In multivariate analysis, high COX-2 expression (P = 0.0005), nonepithelioid cell type (P = 0.002), and chest pain (P = 0.04) were independent predictors of poor prognosis. Furthermore, COX-2 expression contributed in multivariate analysis to both European Organization for Research and Treatment of Cancer (P = 0.001) and Cancer and Leukemia Group B (P = 0.003) prognostic scoring systems. The presence of PGE(2) was demonstrated in all of the samples. These results suggest that COX-2 expression is a prognostic factor in MM. COX-2 is a potential therapeutic target in MM, and trials are required of COX-2 inhibitors alone or in combination with existing treatment modalities.