Prostaglandin endoperoxide synthase 2, also referred to as cyclooxygenase 2 (COX-2), is a key enzyme in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Rat intestinal epithelial (RIE) cells were permanently transfected with a COX-2 expression vector oriented in the sense (RIE-S) or antisense (RIE-AS) direction. The RIE-S cells expressed elevated COX-2 protein levels and demonstrated increased adhesion to extracellular matrix (ECM) proteins. E-cadherin was undetectable in RIE-S cells, but was elevated in parental RIE (RIE-P) and RIE-AS cells. RIE-S cells were resistant to butyrate-induced apoptosis, had elevated BCL2 protein expression, and reduced transforming growth factor beta 2 receptor levels. The phenotypic changes involving both increased adhesion to ECM and inhibition of apoptosis were reversed by sulindac sulfide (a COX inhibitor). These studies demonstrate that overexpression of COX-2 leads to phenotypic changes in intestinal epithelial cells that could enhance their tumorigenic potential.