Several studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of esophageal cancer. The best known function of NSAIDs action is to block the enzyme cyclooxygenase, the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated the expression of cyclooxygenase-2 (Cox-2) in squamous cell cancers of the esophagus and in normal esophageal squamous epithelium. Immunohistochemical detection of Cox-2 revealed strong positive staining in the well-differentiated regions of esophageal tumors, whereas histologically normal squamous epithelium stained only weakly positive. Smooth muscle cells, some stromal and inflammatory cells were also positive. Poorly differentiated areas of the esophageal tumors were negative. Our results suggest that Cox-2 is over-expressed in well-differentiated regions of squamous cell cancers of the esophagus.