The potential use of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancers has been highlighted recently. However, it is not known whether NSAIDs could also be useful for preventing esophageal cancer, although regular users of these drugs appear to have a decreased incidence of esophageal cancer. Therefore, we examined the effect of aspirin on growth and apoptosis in 10 esophageal cancer cell lines as well as the expression and modulation of its target enzymes, cyclooxygenases (COXs), and their product prostaglandin E2. Growth inhibition of these cells by aspirin was dose- and time-dependent and associated with the induction of apoptosis. COX-1 and COX-2 were expressed in 7 of the 10 cell lines. Bile acids could induce COX-2 expression in six of eight cell lines tested, which was correlated with prostaglandin E2 production, and aspirin could inhibit COX-2 enzymatic activity even after bile acid stimulation but was unable to change the COX-2 protein level in these cell lines. Down-regulation of bcl-2 by aspirin was found in the two cell lines tested. These results suggest that induction of apoptosis by aspirin may be a mechanism by which it can intervene in esophageal carcinogenesis and may be indicative of the potential of NSAIDs as chemopreventive agents in esophageal cancer.