The popular over-the counter analgesic drug diclofenac has recently been associated with increased rates of myocardial infarction among patients with cardiovascular risk as well as among healthy populations. Although other traditional non-steroidal anti-inflammatory drugs (tNSAID) have also been accused to exert this risk, literature data at present gives reason to believe that the hazard of myocardial infarction is mainly associated with diclofenac. Large retrospective analyses of clinical data have repeatedly shown that diclofenac, similar as some selective COX-2 inhibitors, increases the propensity to experience adverse cardiovascular and atherothrombotic events. These associations cannot be explained with the deteriorating effect of NSAID on arterial hypertension, as the statistical associations only have been found conclusively for diclofenac and not for other tNSAID. The reasons for this novel side-effect of diclofenac may be based on the specific pharmacology of diclofenac, which, similar to selective COX-2 inhibitors, alters vascular levels of platelet active prostaglandins in a way that favours arterial thrombosis. In this review, we summarize the clinical evidence about adverse atherothrombotic events associated with diclofenac and dissect the pharmacological reasons beyond this phenomenon in comparison to other tNSAID.