BACKGROUND Studies have raised concern on the cardiovascular safety of NSAIDs. We studied safety of NSAID therapy in a nationwide cohort of healthy individuals. METHODS This is a review of the literature regarding cardiovascular safety of NSAIDs with special focus on the few studies investigating healthy individuals. RESULTS Due to a high frequency of gastrointestinal complications related to NSAID treatment a new generation of NSAID, called the selective COX-2 inhibitors, were developed in order to use the beneficial pain-relieving effect of NSAIDs without the COX-1 related risk of gastrointestinal bleeding. However, the selective COX-2 inhibitor rofecoxib was withdrawn from the market in 2004 after studies had documented an increased risk of myocardial infarction related to this drug. Focus also turned to the traditional NSAIDs and found similar results for some of the older drugs, especially diclofenac and high-dose ibuprofen. Most interventional studies have not been designed specifically to evaluate the cardiovascular safety of NSAIDs and no studies have previously investigated the relationship between NSAID treatment and cardiovascular risk in healthy individuals. Overall, evidence regarding the selective COX-2 inhibitors' cardiovascular risk profile (mostly thrombo-embolic events) is derived from the clinical trials whereas results on the traditional NSAIDs are based on observational studies and meta-analyses. Importantly, some of the randomized trials comparing COX-2 inhibitors with traditional NSAIDs did not show a difference in cardiovascular risk and it cannot be denied that the traditional NSAIDs are characterized by a different cardiovascular risk-profile than the COX-2 inhibitors. A recent cohort study among one million healthy people showed that the selective COX-2 inhibitors as well as diclofenac are associated with an increased risk of death or myocardial infarction. This was further underlined by a dose-response relationship. CONCLUSIONS Individual NSAIDs have different cardiovascular safety that needs to be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals. This notion is also valid for healthy individuals and underlines the importance of critical use of NSAID therapy in the general population and also that over-the-counter retail of NSAIDs should be reassessed.