Side effects of the distal gastrointestinal tract after NSAID use are common and more frequent than previously recognized. Increased mucosal permeability and mucosal inflammation are often silent but appear after NSAID treatment with most dual COX inhibitors. Other clinical manifestations include: anemia, occult blood loss, malabsorption, proteinloss, ileal dysfunction, diarrhea, mucosal ulceration and strictures due to diaphragm disease. More common complications are lower gastrointestinal bleeding and perforation, which represent at least one third of all gastrointestinal complications observed with NSAID use. Studies with selective COX-2 inhibitors have shown that, in the short term, these agents do not increase mucosal permeability or induce anemia due to occult bleeding and that, when compared to dual COX inhibitors, lower gastrointestinal complications may be reduced by 50%. In order to minimize the impact of these side effects, it is important to increase the current standards of suspicion by physicians who treat these patients, since drug discontinuation may further reduce damage, and clinical experience with agents that may prevent or treat distal tract damage is very limited. From this perspective, selective COX-2 inhibitors may be the drugs of choice in the high-risk patient that needs NSAIDs. Another important area of uncertainty is the impact of NSAID use in patients with inflammatory bowel diseases. Data from different animal models of inflammatory bowel disease suggest that inhibition of both COX-1 and COX-2 derived prostaglandins affects the severity of the mucosal inflammation. However, current epidemiological and clinical data are contradictory. Since many patients with inflammatory bowel diseases need NSAID treatment, clinicians should be aware of the problem and try to minimize or reduce NSAID exposure. Further studies are needed to define the effect of both non-selective NSAIDs and selective COX-2 inhibitors in these patients.