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Over the past decades, the medical community has witnessed a significant improvement in cardiovascular disease (CVD) outcomes. Nonetheless, CVD remains a leading cause of morbidity and mortality globally. Prevention strategies must address all aspects of a patient’s lifestyle habits, including healthy nutrition, physical activity, smoking cessation, and stress reduction.1 When an individual’s risk is sufficiently high, pharmacologic therapy is often considered to reduce CVD risk as part of a shared decision-making process for optimal CVD prevention. Aspirin is a cornerstone of antiplatelet therapy for the secondary prevention of CVD, but its role in primary prevention remains uncertain. Over the past several decades, there has been great interest to identify individuals for whom the clinical benefit of aspirin for the prevention of a first heart attack or stroke (primary prevention) exceeds the risk of bleeding. Meta-analyses of early primary prevention trials of aspirin suggested a modest benefit of low-dose aspirin in the prevention of first heart attack or stroke at the cost of excess major bleeding.2,3 In fact, the number needed to treat to prevent a single cardiovascular event was comparable to the number needed to harm by causing 1 major bleeding event. Thus, early guidelines recommended low-dose aspirin only for individuals with high CVD risk when the benefit would exceed the risk. Over time, larger trials investigating the benefit vs risk of low-dose aspirin were designed in individuals with higher CVD risk, including older adults, individuals with diabetes, and individuals with subclinical CVD.4 Despite the enrollment of individuals with higher risk, the results were consistent: the clinical benefit of aspirin was marginal and, in most individuals, the benefit was offset by the excess risk of bleeding. Based on cumulative data, the US Preventive Services Task Force (USPSTF) updated its 2016 recommendations on the use of aspirin for the primary prevention of CVD.5 The 2022 USPSTF recommendations6-8 suggest that the decision to initiate low-dose aspirin for the primary prevention of CVD in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one (C statement), and recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults aged 60 years or older (D statement). While the new USPSTF recommendations6-8 have some distinguishing features from the 2016 recommendations,5 including changing the age ranges and statement grades on aspirin use, and stating that the evidence is inadequate that low-dose aspirin use reduces colorectal cancer incidence and mortality, the overall message and recommendations are largely consistent with regard to individualized decision-making. Both the 2016 and 2021 recommendations5-8 remind us that the clinical benefit of low-dose aspirin for primary prevention is marginal and must be carefully balanced against the well-known excess risk of major bleeding. Consistent with the USPSTF approach,6-8 other guidelines recommend a tailored decisionmaking process between the patient and the health care professional based on the potential benefit vs risk. The American College of Cardiology and American Heart Association recommend that low-dose aspirin use (75 to 100 mg/d) might be considered for the primary prevention of atherosclerotic CVD among select adults ages 40 to 70 years at higher CVD risk but not at increased risk of bleeding.1 Low-dose aspirin use is not recommended on a routine basis for primary prevention of CVD in adults older than 70 years, or among adults of any age who are at increased risk of bleeding. The European Society of Cardiology suggests that among individuals at very high CVD risk, low-dose aspirin may be considered for primary prevention.9 The American Academy of Family Physicians supports the 2016 USPSTF recommendation on aspirin use.10 + Related articles at jama.com, jamainternalmedicine.com