BACKGROUND: Evidence indicates that aspirin is effective for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC) but also increases the risk for gastrointestinal (GI) and cerebral hemorrhages. OBJECTIVE: To assess the net balance of benefits and harms from routine aspirin use across clinically relevant age, sex, and CVD risk groups. DESIGN: Decision analysis using a microsimulation model. DATA SOURCES: 3 systematic evidence reviews. TARGET POPULATION: Men and women aged 40 to 79 years with a 10-year CVD risk of 20% or less, and no history of CVD and without elevated risk for GI or cerebral hemorrhages that would contraindicate aspirin use. TIME HORIZON: Lifetime, 20 years, and 10 years. PERSPECTIVE: Clinical. INTERVENTION: Low-dose aspirin (=100 mg/d). OUTCOME MEASURES: Primary outcomes are length and quality of life measured in net life-years and quality-adjusted life-years. Benefits include reduced nonfatal myocardial infarction, nonfatal ischemic stroke, fatal CVD, CRC incidence, and CRC mortality. Harms include increased fatal and nonfatal GI bleeding and hemorrhagic stroke. RESULTS OF BASE-CASE ANALYSIS: Lifetime net quality-adjusted life-years are positive for most adults initiating aspirin at ages 40 to 69 years, and life expectancy gains are expected for most men and women initiating aspirin at ages 40 to 59 years and 60 to 69 years with higher CVD risk. Harms may exceed benefits for persons starting aspirin in their 70s and for many during the first 10 to 20 years of use. RESULTS OF SENSITIVITY ANALYSIS: Results are most sensitive to the relative risk for hemorrhagic stroke and CVD mortality but are affected by all relative risk estimates, baseline GI bleeding incidence and case-fatality rates, and disutilities associated with aspirin use. LIMITATIONS: Aspirin effects by age are uncertain. Stroke benefits are conservatively estimated. Gastrointestinal bleeding incidence and case-fatality rates account only for age and sex. CONCLUSION: Lifetime aspirin use for primary prevention initiated at younger ages (40 to 69 years) and in persons with higher CVD risk shows the greatest potential for positive net benefit. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.