Platelet activation and aggregation play a critical role in thrombosis, a fundamental pathophysiologic event responsible for the acute clinical manifestations of atherothrombotic events such as acute coronary syndrome, myocardial infarction, ischemic stroke/transient ischemic attack and peripheral artery disease. Dual antiplatelet therapy (low-dose aspirin plus ADP-P2Y12 receptor blockers) has become the cornerstone of therapy for the management of acute and chronic coronary artery disease and the prevention of ischemic complications associated with percutaneous coronary intervention. However, dual antiplatelet therapy in primary prevention of cardiovascular disease in patients without known cardiovascular disease did not significantly reduce the risk of cardiovascular events, such as myocardial infarction, stroke or death, but significantly increased the rate of bleeding. Furthermore, despite multiple randomized controlled trials evaluating the efficacy and safety of aspirin use in patients without known cardiovascular disease, its role in primary prevention is still unclear, especially in patients with a higher risk of cardiovascular disease (non-diabetic individuals with >2 risk factors for coronary artery disease, elderly >60 years with additional risk factors, and patients with diabetes). Currently, there are four ongoing randomized controlled trials aiming to fill the missing gap in the efficacy and safety of aspirin therapy for primary prevention in these patients. The current European and United States Guidelines agree that primary prevention of cardiovascular disease is essential, but there are some substantial differences in risk estimation and treatment strategies among patients without known cardiovascular disease. This short review is focused on these differences and practical treatment approach to these patients based on present European and United States recommendations.