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Nonsteroidal anti-inflammatory drugs (NSAIDs) produce significant gastrointestinal (GI) adverse events. Laboratory and clinical studies suggest that NSAIDs have the potential to trigger the onset or relapse of inflammatory bowel disease. In this review, the currently available information on the mechanism of action of NSAID injury of the GI tract and the pathophysiology of GI effects of NSAIDs, including immune dysregulation will be assessed. A detailed description of NSAID effects on individual GI organs will be discussed. This is followed by a MEDLINE review of clinical literature on the relationship between NSAID ingestion and the development and worsening of inflammatory bowel disease.