BACKGROUND: Evidence indicates that aspirin is effective for preventing the first incidence (i.e., primary prevention) of cardiovascular disease (CVD) but regular use also increases risk for major gastrointestinal (GI) and cerebral hemorrhages. OBJECTIVE: To assess the net balance of benefits and harms from initiating routine use of aspirin for primary prevention across clinically relevant age, sex, and CVD risk groups. DESIGN: Decision analysis using a microsimulation model. DATA SOURCES: Relative risks of aspirin benefits and harms are sourced from an updated systematic evidence review. TARGET POPULATION: Men and women aged 40 to 79 years with 10-year CVD risk of 20 percent or less, no history of CVD, and non-elevated risk for major GI or cerebral hemorrhage. TIME HORIZON: Lifetime and 10 years. PERSPECTIVE: Clinical. INTERVENTION: Daily use of low-dose aspirin (100mg or less). Lifetime use and stopping at 5-year age intervals between ages 65-85 years were considered as separate interventions. OUTCOME MEASURES: Primary outcomes were net benefits measured in quality-adjusted life years (QALYs) and life years. Aspirin benefits considered included reduction of non-fatal myocardial infarction and non-fatal ischemic stroke. Aspirin harms considered included increase in non-fatal major GI bleeding and intracranial hemorrhage. The potential for benefits of reduced CVD mortality and CRC incidence and the potential harm of increased fatal major GI bleeding were considered in sensitivity analyses. RESULTS OF BASE CASE ANALYSIS: When measured in QALYs, the lifetime net benefits from taking low-dose aspirin for primary prevention were positive for both men and women at ≥5% 10-year CVD risk levels when starting between ages 40-59 years and at ≥10% 10-year CVD risk levels when starting between ages 60-69 years. Lifetime gains in net QALYs with aspirin use ranged from 2.3 to 66.2 per 1,000 persons in these groups. Lifetime net benefits of starting aspirin measured in life years were positive for men at ≥5% and women at ≥10% 10-year CVD risk levels at ages 40-49 years, and they were positive for men at ≥7.5% and women at ≥15% 10-year CVD risk levels at ages 50-59 years. Lifetime gains in life years with aspirin use ranged from 0.4 to 52.4 net life years per 1,000 persons in these groups. Lifetime net life years were negative in most cases for persons starting aspirin between ages 60-69 years, and both measures of lifetime net benefit were generally negative for persons aged 70-79 years when starting aspirin. Stopping aspirin at 5-year intervals between ages 65-85 years showed little advantage compared to lifetime (or no) use. For most groups, aspirin harms realized in the first 10 years of use were expected to outweigh benefits realized in the first 10 years. For the groups that realized positive net benefit within 10 years of use, the net benefit was small. RESULTS OF SENSITIVITY ANALYSIS: Substantial variation in lifetime net QALYs and life years was found with alternative assumptions regarding aspirin’s possible effect on CRC incidence, CVD mortality, and fatal major GI bleeding, though there was insufficient evidence of such effects using established USPSTF methods. Separate analyses that assumed aspirin i) reduces CRC incidence after 10 years of use or ii) reduces CVD mortality both showed moderate-to-large increases in lifetime net benefit relative to the base case analysis. When it was assumed that aspirin increases the risk of fatal major GI bleeding at the same proportion as non-fatal major GI bleeding, we found moderate reductions in estimated lifetime net benefit. Even small levels of disutility associated with routine use of aspirin led to moderate-to-large reductions in lifetime net QALYs. LIMITATIONS: Sensitivity analyses demonstrate that findings are sensitive to uncertainty about aspirin’s effects when used for primary prevention—particularly, whether aspirin reduces the risk for CRC incidence and affects fatal major GI bleeding risks. Some factors that may be correlated with CVD risk—such as blood pressure, current smoking, and diabetes—could not be accounted for in estimating major GI bleeding risks in a U.S. primary prevention population. Persons aged 40-49 and 70-79 years are not as well represented in primary prevention aspirin trials, making it less clear how aspirin use may affect these groups. Lack of validated prediction of CVD and bleeding risks by race/ethnicity limits the ability to report on these potentially important differences. CONCLUSIONS: This updated decision analysis found many of the same population groups previously favored for aspirin initiation could expect positive lifetime net benefits of using aspirin for primary prevention. However, the quantitative margins for net benefit were generally much smaller in this updated decision analysis. This change in base case findings was driven by the removal of a beneficial effect of aspirin on CRC incidence, due to insufficient evidence for this outcome found by the updated systematic review. Uncertainty in influential factors related to net benefit notwithstanding, this decision analysis finds that men and women aged 40-59 years and with ≥10% 10-year ASCVD risk were most likely to see lifetime benefit from using aspirin for primary prevention and that adults aged 70-79 years with ≤20% 10-year ASCVD risk were most likely to experience net harm from starting aspirin.