BACKGROUND: Smoking modulates inflammatory bowel disease, protecting from ulcerative colitis on the one hand and worsening the course of Crohn's disease on the other. This influence might occur through changes in intestinal permeability, because permeability is increased in most patients with Crohn's disease. AIM: To study the influence of smoking on small intestinal permeability and its increase induced by indomethacin. METHODS: 50 smokers and 50 nonsmokers underwent a 51Cr-EDTA basal permeability test and the same test after challenge with indomethacin 125 mg p.o. RESULTS: Small intestinal permeability was the same in smokers (median 1.22%; IQR 1.00-1.58) and nonsmokers (1.24%; 0.94-1.66). Basal small intestinal permeability was lower in females (1.09%; 0.87-1.33) than in males (1.48%; 1.18-1.88). Indomethacin challenge increased permeability by 110% (71-141) in smokers, vs. 156% (78-220) in the nonsmokers (P=0.04). CONCLUSION: Smoking reduces the effect of NSAID on small intestinal permeability. It is therefore unlikely that the adverse effect of smoking on Crohn's disease is related to its influence on intestinal permeability.