The interactions of cigarette smoking with COX-2 on colitis and colitis-associated adenoma formation were studied. Mice were induced with colitis and exposed to cigarette smoke (CS) and/or SC236 (a COX-2 inhibitor). Results indicated that CS did not alter acute colonic inflammation. Addition of SC236 abolished the induction of proliferation and oxidative damage by colitis. Chronic SC236 treatment abolished the promoting effect of CS on colonic adenoma formation, via suppression of COX-2- and VEGF-mediated proliferation and angiogenesis, and reversed bcl-2-mediated inhibition of apoptosis by CS. To conclude, COX-2 inhibitor could be an implication on cancer prevention in smokers with chronic colitis.