Aspirin is now widely accepted as the first-line antithrombotic platelet therapy for at-risk individuals. During the last decade or so it has also become established that co-administering antagonists of the ADP receptor P2Y(12) with aspirin further reduces the risk of acute thrombotic events. By the nature of its evolution, this therapeutic approach assumes that P2Y(12) receptor antagonists will be added to aspirin, and this therefore dominates the design of clinical trials. This strategy has resulted in the generation of a large body of clinical evidence showing the benefit of aspirin plus P2Y(12) receptor antagonists, largely from studies with clopidogrel and more recently from those with prasugrel and ticagrelor, but with obvious limitations in terms of residual ischaemic event rates and bleeding complications. It is our hypothesis, however, that when administered in the presence of potent P2Y(12) receptor antagonists, aspirin could actually increase total cardiovascular risk, although this has never been tested in large outcome studies. Clearly, this potentially negative interaction could be of relevance to millions of patients.