Summary In patients at high risk of NSAID‐associated serious upper gastrointestinal complications, gastroprotection with misoprostol or a proton pump inhibitor should be considered. Only misoprostol, 800 µg/day, has been shown to reduce serious upper gastrointestinal complications in a large clinical outcome trial. The benefit of Helicobacter pylori eradication in reducing NSAID‐associated gastrointestinal toxicity is controversial, and routine testing for and eradication of H. pylori in NSAID users are not currently advised. The gastrointestinal safety of rofecoxib and celecoxib has been assessed in large clinical outcome trials which, on first analysis, show benefits over non‐selective NSAIDs in the incidence of serious upper gastrointestinal complications. However, longer term gastrointestinal data from the celecoxib study (CLASS) and cardiovascular adverse event data from the rofecoxib study (VIGOR) have questioned the risk–benefit profile of these new drugs and, until they are better understood, it seems sensible not to use them routinely in large numbers of individuals. The gastrointestinal safety of meloxicam and etodolac has not been adequately assessed in such trials. Therefore, evidence for their use instead of non‐selective NSAIDs, or instead of celecoxib or rofecoxib, is not robust.