Cyclo-oxygenase (COX)-2 is not usually detectable in normal tissues but is induced in inflammation and carcinogenesis. The level of COX-2 is elevated in cancer tissues of the colon, bladder, and skin. In the esophagus, squamous cell carcinoma and adenocarcinoma are known to express COX-2. The purpose of this study was to clarify the association of COX-2 expression with clinicopathological factors of squamous cell carcinoma. The immunohistochemical expression of COX-2 was examined in 48 surgical specimens of esophageal squamous cell carcinoma. Although COX-2 over-expression was more frequently observed in tumors invading the submucosa (T1b, 76.4%), muscularis propria (T2, 57.1%), adventitia, or adjacent organs (T3 approximately 4, 83.3%), even 33.3% of mucosal cancers, such as T1a, showed COX-2 over-expression. COX-2 over-expression was present in 82.3% of lymph node-negative patients but in only 54.8% of lymph node positive patients. There was no difference in COX-2 over-expression between the earlier stages (0 and I, 60%) and more advanced stages (II approximately IV, 69.6%). COX-2 over-expression did not correlate with survival during 3 years of follow-up. These findings suggest that COX-2 is associated with the phenotype of the esophageal squamous cell carcinoma cells, including superficial cancer cells, and may be related to tumor growth in esophageal squamous cell carcinoma.