The significance of cyclooxygenase-2 (COX-2) expression in mesenchymal tumors has not been completely described. We analyzed clinicopathologic variables and COX-2 protein expression in all mesenchymal tumors of the GI tract that were treated at our institution between 1990 and 2002. Paraffin-embedded specimens were immunohistochemically stained for KIT and COX-2 protein. KIT-positive tumors were diagnosed as gastrointestinal stromal tumors (GIST). Among 42 available specimens, 38 tumors were diagnosed as GIST and four were non-GIST mesenchymal GI tumors (KIT negative). The median overall survival for the GIST patients was 34 months. Ninety-two percent of GIST expressed COX-2 protein. COX-2 protein was not expressed in any of the non-GIST tumors. GIST patients with negative or low COX-2 expression developed disease recurrence and/or died of their disease in 37% of the cases, compared with 18% for GIST patients with high COX-2 expression (difference not statistically significant). The vast majority of mesenchymal tumors of the GI tract are GIST that express COX-2 protein. As opposed to known predictors of GIST behavior such as tumor size and mitotic count, levels of COX-2 protein expression did not correlate with clinical outcome. © 2006 The Society for Surgery of the Alimentary Tract Published by Elsevier Inc.