OBJECTIVE Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. METHODS Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. RESULTS Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. CONCLUSIONS Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile.