In the context of secondary prevention, the efficacy of aspirin in reducing cardiovascular events is widely acknowledged. However, its use for primary prevention is still debated because of uncertain data regarding the risk-benefit ratio. Despite the reduction in atherothrombotic events, almost all randomized clinical trials and meta-analyses have failed to demonstrate a net clinical benefit, as cardiovascular outcome improvement was counterbalanced by increased bleeding. We have, however, to acknowledge that, within the population eligible for primary prevention, cardiovascular risk distribution is extremely heterogeneous. Using data obtained from the most recent trials, we performed a meta-regression of benefits and risks associated with aspirin related to 10-year risk of major adverse cardiovascular events (MACEs). We are thus proposing a tailored approach to find the proper patient category to treat with aspirin in primary prevention. In patients <70 years old with an optimal control of cardiovascular risk factors, physicians should carefully evaluate individual MACE risk and make a therapeutic decision accordingly, also considering bleeding risk and patient preference. The results of net clinical benefit analysis of aspirin therapy suggest that patients with intermediate-high cardiovascular risk (10-year MACE risk >10%) without a prohibitive bleeding risk may represent the target population, since in these patients the reduction in atherothrombotic events overcomes the induced excess of bleeding. Antiplatelet therapy benefits also appear to be amplified by the simultaneous administration of gastroprotective agents and treatment of other cardiovascular risk factors, such as dyslipidemia and hypertension.