The widespread use of nonselective NSAIDs and cyclo-oxygenase (COX)-2 inhibitors has a substantial impact on healthcare budgets worldwide. The cost of their gastrointestinal (GI) adverse effects is a major component of their direct cost and has received much attention in the literature. Published studies have often differed in their methodologies and results. It is important for decision makers to understand the reasons for these differences in order to make informed decisions. We conducted a literature review to summarise data that evaluate the direct costs of NSAID-related GI adverse effects worldwide. This resulted in 789 articles from which 29 studies met the inclusion criteria and were fully reviewed. Of these 29, the 9 studies that assessed the cost of COX-2 inhibitors were all based on decision economic models, compared with only 7 of the remaining 20 studies, which assessed the cost of nonselective NSAIDs. In most studies, the perspective was that of the healthcare payer and the costs assessed were reimbursement costs. Costs of GI events almost doubled between regular users and non-users of nonselective NSAIDs and were much higher in high-dose versus low-dose users. The ratio of the total cost of nonselective NSAIDs to their acquisition cost reported in all studies varied from 1.36 to 2.12. Both of these numbers were reported in one single study assessing several different NSAIDs in France. Thus, the GI adverse events attributable to nonselective NSAIDs are substantial, and their costs often exceed the cost of the nonselective NSAID itself.The acquisition cost of the COX-2 inhibitors was the main driver of their total cost. The GI adverse effects with the COX-2 inhibitors added 10-20% to their acquisition cost in North America, while this increase was about 50% in some European countries. Decision analysis models showed that the direct costs of COX-2 inhibitors were lower than those of nonselective NSAIDs in patients at risk of NSAID gastropathy but higher in patients at no to low risk of gastropathy. Thus, from an economic perspective, the healthcare system would benefit from treating patients at risk of NSAID gastropathy with COX-2 inhibitors, but not those at no to low risk.