Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of clinically important upper gastrointestinal ulcers and bleeds about fourfold. Other risk factors for these events include advanced age, higher NSAID dose, prior ulcer or bleed, use of anticoagulants, use of corticosteroids, and poor general health. Among NSAID users with more than one risk factor, the incidence of serious ulcer complications may be as high as 4% to 8% per year. NSAIDs may also increase blood pressure and have adverse effects on renal function. NSAID-associated toxicity may be decreased by (1) trying less toxic alternative drugs; (2) using NSAIDs less frequently or at a lower dose; (3) use of cotherapy, such as misoprostol or proton pump inhibitors, to prevent complications; (4) or use of the more selective cyclooxygenase-2 inhibitors. More research is needed to determine which of these strategies or combination of strategies is optimal in terms of patient safety and cost.