Significance Our study not only reveals a novel role of peroxisome proliferator-activated receptor δ (PPARδ) in colonic inflammation and colitis-associated tumorigenesis, but also provides some rationale for development of PPARδ antagonists as new therapeutic agents in the treatment of inflammatory bowel disease and colitis-associated colorectal cancer. Moreover, our findings indicate that prostaglandin E 2 generated by chronic inflammation is a crucial mediator connecting chronic inflammation and colorectal carcinogenesis.