Cyclooxygenase-2 (COX-2) is an important regulator of inflammation implicated in the development of a variety of diseases, including inflammatory bowel disease (IBD). However, the regulation of intestinal inflammation by COX-2 is poorly understood. We previously reported that COX-2^−/− mice fed a cholate-containing high-fat (CCHF) diet had high mortality of unknown mechanisms attributable to severe intestinal inflammation in the ileo-ceco-colic junction that presented characteristics similar to Crohn's disease (CD). To further characterize the role of COX-2 in intestinal inflammation, we established cell-specific conditional COX-2^−/− mice. Endothelial cell-specific (COX-2^−E/−E) and myeloid cell-specific (COX-2^−M/−M) COX-2^−/− mice, but not wild-type mice, on the CCHF diet developed localized CD-like pathology at the ileo-ceco-colic junction that was associated with cellular infiltration, increased expression of myeloperoxidase and IL-5, and decreased IL-10 expression. The CD-like pathology in COX-2^−E/−E mice was also accompanied by increased expression of cytokines (IL-6, TNF-α, and INF-γ), compared with wild-type mice and COX-2^−M/−M mice. In contrast, the ileo-ceco-colic inflammation in COX-2^−M/−M mice was associated with more pronounced infiltration of granulocytes and macrophages than COX-2^−E/−E mice. COX-2^−ME/−ME (COX-2^−M/−M × COX-2^−E/−E) mice on the CCHF diet developed CD-like pathology in the ileo-ceco-colic junction reminiscent of total COX-2^−/− mice on CCHF diet and wild-type mice on CCHF diet treated with COX-2 inhibitor, celecoxib. The pathology of diet-mediated ileo-ceco-colic inflammation in COX-2^−/− mice offers an excellent model system to elucidate the protective roles of endothelial and myeloid COX-2 and the molecular pathogenesis of CD.