Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage arthritis. While controlling symptoms and improving quality of life, NSAID use is associated with gastroduodenal injury and a 2%-4% annual risk for symptomatic gastroduodenal ulceration, hemorrhage, and perforation. This requires clinicians to balance the efficacy of NSAIDs against the potential risk of serious gastrointestinal events. Identification and stratification of risk can help guide the optimal approach for arthritis management of individual patients or large populations such as managed care organizations. NSAID-induced gastroenteropathy carries considerable economic consequences; 46% of arthritis costs are related to managing serious adverse events. It is reasonable to assume that these costs may not be incurred if high-risk patients are recognized and optimally managed. Newer therapies with proven safety margins present an attractive option, especially for patients at higher risk. The single-tablet formulations of diclofenac and misoprostol (Arthrotec) offer an alternative in managing NSAID patients because of their inherent safety profile. Studies with diclofenac/misoprostol indicate its effectiveness in treating signs and symptoms of arthritis and in reducing the incidence of NSAID-induced gastroenteropathy. As such, this agent may provide improved medical and economic outcomes. This review discusses the clinical aspects of NSAID-induced gastroenteropathy, including available preventive therapies. Approaches to assessing patients' risk for developing complications, and the relationship of medical risk and economic outcomes, are also examined. Although not all patients require preventive therapy, patients with heightened risk may benefit clinically and economically from gastroprotective NSAIDs. Additional research or modeling may provide further insight into the economic implications of managing and preventing NSAID-induced gastroenteropathy.