The linkage between gastroduodenal mucosal injury and nonsteroidal anti-inflammatory drugs (NSAIDs) is now well established. Fifteen percent to 20% of patients taking these agents develop gastric or duodenal ulcer, and about 3% of this group goes on to experience hemorrhage or perforation. Gastrointestinal (GI) complications occur primarily in certain high risk groups, notably elderly female patients and patients with a prior history of peptic ulcer or GI bleeding. Recently, two new NSAIDs, nabumetone and etodolac, which are reportedly safer because they selectively inhibit prostaglandin synthesis in target tissues but spare that in the stomach, have been introduced in the United States. Further, data from clinical trials of oxaprozin, an NSAID not yet available in the United States, indicate that this agent may have a better safety profile than older NSAIDs. A review of the literature concerning the mucosal toxicity of these three agents reveals that the overall ulceration and major complication rate is low. However, a direct comparison with older NSAIDS in a large group of patients in a dose with similar efficacy is lacking.