Like all COX-2 inhibitors, rofecoxib has been developed based on the hypothesis that at comparable therapeutic efficacy, it would have a better safety and tolerability profile than conventional NSAIDs. The Vioxx GI Outcomes Research trial has demonstrated that rofecoxib is indeed safer for the gastrointestinal tract than NSAIDs. However, this study has also raised questions regarding the cardiovascular safety of rofecoxib. Thereafter, several epidemiological and case-control studies have reinforced the association between rofecoxib and a higher risk of cardiovascular events. However, at this time, no prospective controlled study is available to conclude definitively on this issue. Several pathogenic mechanisms are evoked to explain why rofecoxib increases the cardiovascular risk. These include the development of a prothrombotic state, a sodium retention and an increase in systemic blood pressure. Recently, new evidence have become available indicating that rofecoxib indeed increases the number of thrombo-embolic events. These data have resulted in the complete withdrawal of rofecoxib from the market. Was it scientifically reasonable to withdraw rofecoxib rather than to adapt its label? Is the safety profile of rofecoxib really much worse than that of aspirin or other traditional NSAIDs? The main consequence of this withdrawal is a considerable threat on the entire class of selective COX-2 inhibitors without a clear evaluation of the balance between the risks and benefits of these compounds.