Cyclooxygenase-2 (COX-2) is involved in esophageal carcinogenesis, but its clinical significance is not clarified yet. The association of several clinicopathological parameters with the immunohistochemical expression of COX-2 was analyzed in paraffin-embedded esophageal cancer specimens. In adenocarcinomas, COX-2 upregulation showed to be a late event and in a multivariate analysis it was associated independently with a reduced survival after surgery compared with low COX-2 expressed tumors (P=0.02). Although, the expression was extensively high in well-differentiated parts of squamous cell carcinoma, it was not related with a poor outcome. This study supports further investigation of selective COX-2 inhibitors in these tumors.