Osteoarthritis is an increasingly prevalent disorder with an incidence rate that rises sharply with age. Unfortunately, the most commonly used medications for providing symptomatic relief, nonsteroidal anti-inflammatory drugs (NSAIDs), can cause significant gastrointestinal (GI) ulceration. There is recent evidence that agents commonly employed to protect the upper GI tract actually increase the incidence and severity of ulceration and bleeding in the lower intestine. Intestinal injury is more difficult to diagnose and treat than upper GI damage, and symptoms correlate poorly with the severity of tissue injury. Moreover, use of low-dose aspirin for cardioprotection (a common co-treatment with the selective cyclooxygenase-2 inhibitors) further augments intestinal damage, particularly when enteric-coated aspirin is used. Thus, by focusing entirely on prevention of NSAID-induced damage to the upper GI tract, physicians may be inadvertently placing their patients at risk of serious, difficult-to-diagnose injury for which there are no proven-effective therapies and are associated with significantly higher rates of morbidity and mortality.