Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors (Coxibs) are commonly used for minor pain treatment and chronically in the management of rheumatoid arthritis and osteoarthritis. Three areas of safety concerns are shared by both groups of drugs: Gastrointestinal complications (upper gastrointestinal bleeding, perforations or obstruction), cardiovascular safety (mainly myocardial infarction) and renal safety (acute renal failure, hypertension and electrolyte abnormalities). The incidence of renal complications may be increased two-fold with NSAIDs or coxibs, and there is no evidence for a major difference between the two groups of drugs. Coxibs are clearly associated with improved gastrointestinal safety compared to NSAIDs, but this benefit is reduced and may be lost completely with concurrent low-dose aspirin use. In contrast, coxibs may be associated with a greater incidence of cardiovascular complications, mainly myocardial infarction, especially in comparison to certain NSAIDs such as naproxen. Thus, coxibs are not generally safer than NSAIDs. Rather, their long-term use should be customized to individual patients and their intrinsic baseline risks and other medications required in their management.