Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, analgesic, and anti-pyretic effects, whereas low-dose aspirin (also an NSAID) is used for cardiovascular prophylaxis. The main concern limiting use of these drugs is their gastrointestinal (GI) toxicity. GI side effects include ulcers (found at endoscopy in 15%-30% of patients using NSAIDs regularly), complications such as upper GI bleeding (annual incidence of 1.0%-1.5%), and development of upper GI symptoms such as dyspepsia (occurring in up to 60% of patients taking NSAIDs). Histamine-2 receptor antagonists are not effective at preventing NSAID-induced gastric ulcers when used at standard doses, although they can decrease upper GI symptoms. Misoprostol effectively decreases NSAID-induced ulcers and GI complications but is used infrequently in the United States-perhaps because of issues of compliance (multiple daily doses) and side effects (eg, diarrhea, dyspepsia). Once-daily proton pump inhibitor (PPI) therapy also decreases the development of NSAID-associated ulcers and recurrent NSAID-related ulcer complications; it also decreases upper GI symptoms in NSAID users. In patients using aspirin, the addition of a cyclooxygenase-2-specific inhibitor appears to significantly increase GI risk to the level of a nonselective NSAID; aspirin plus a nonselective NSAID appears to increase GI risk still higher. Patients taking low-dose aspirin who have risk factors for GI complications (including concomitant nonselective NSAID therapy) should receive medical co-therapy, such as a PPI.