Cardiovascular disease (CVD) is the leading cause of death in the United States. To update a systematic review about the benefits of aspirin for the primary prevention of cardiovascular events in adults aged 40 years or older and to evaluate effect modification in subpopulations. MEDLINE, PubMed, Cochrane Central Register of Controlled Trials (January 2008 to January 2015), and Cochrane Database of Systematic Reviews. Two investigators independently reviewed 3396 abstracts and 65 articles according to prespecified criteria. All included trials evaluated aspirin for the primary prevention of cardiovascular events. Two investigators assessed study quality; data were abstracted by 1 reviewer and checked by a second. Two good-quality and 9 fair-quality randomized, controlled trials were identified. In analyses of all doses, aspirin reduced the risk for nonfatal myocardial infarction (MI) (relative risk RR, 0.78 95% CI, 0.71 to 0.87) but not nonfatal stroke; aspirin showed little or no benefit for all-cause or cardiovascular mortality. Benefits began within the first 5 years. Older adults achieved greater relative MI reduction, but no other effect modifications were found in analyzed subpopulations. In trials with aspirin doses of 100 mg or less per day, the reduction in nonfatal MI benefit persisted (absolute risk reduction, 0.15 to 1.43 events per 1000 person-years) and a 14% reduction in nonfatal stroke benefit was noted, but no benefit was found for all-cause mortality (RR, 0.95 CI, 0.89 to 1.01) or cardiovascular mortality (RR, 0.97 CI, 0.85 to 1.10). Evidence for aspirin in primary prevention is heterogeneous and limited by rare events and few credible subgroup analyses. The beneficial effect of aspirin for the primary prevention of CVD is modest and occurs at doses of 100 mg or less per day. Older adults seem to achieve a greater relative MI benefit. Agency for Healthcare Research and Quality.