Evidence indicates that aspirin is effective for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC), but regular use also increases risk for gastrointestinal (GI) and cerebral hemorrhages. To assess the net balance of benefits and harms from routine use of aspirin for primary prevention across clinically relevant age, sex, and CVD risk groups. Decision analysis using a microsimulation model. Relative risks of aspirin benefits and harms are sourced from three updated systematic evidence reviews. 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 GI or cerebral hemorrhage. Lifetime, 20 years, and 10 years. Clinical. Daily use of low-dose aspirin (100mg or less). Primary outcomes are net benefits in terms of life years and quality-adjusted life years (QALYs). Benefits include reduction of non-fatal myocardial infarction, non-fatal ischemic stroke, fatal CVD, CRC incidence, and CRC mortality. Harms include increase in fatal and non-fatal GI bleeding and hemorrhagic stroke. Lifetime net benefits from routine aspirin use for primary prevention are found to be positive for men and women aged 40-69 in all 10-year CVD risk levels. For men and women aged 70-79, lifetime net outcomes are mixed: net life years are negative, but net QALYs are positive. The largest lifetime net benefits from aspirin are found among men and women aged 40-59 with moderate-to-high baseline CVD risk. Net benefits from aspirin over 10 and 20 years of use are generally much lower and may be negative. Net benefit calculations also favor early over delayed initiation of aspirin use for all men and women aged 40-69. Net benefit results are most sensitive to uncertainty regarding the effect of low-dose aspirin on the increased risk of hemorrhagic stroke and in the primary prevention of CVD mortality. Imposing small disutilities on routine aspirin use can substantially diminish the net benefit of using aspirin to improve overall quality of life. Sensitivity analyses demonstrate that our current imprecision in understanding aspirin's effects on benefits and harms, when used for primary prevention, carry through to model estimates. Persons aged 40-49 are not as well represented in the studies informing aspirin's effects, and therefore, the modeling results may not reliably apply to persons in this age group. Improved ability to estimate individual GI bleeding risk would enhance precision. Modeled results do not account for potential correlations between CVD risk factors and GI bleeding risk, except for age and sex. Benefits are predicted to exceed harms among persons aged 40-69 with non-elevated bleeding risk who take aspirin for primary prevention of CVD and CRC over their lifetimes. Net benefits from routine aspirin use over a 10- or 20-year horizon are expected to be substantially smaller, and in many cases, harms may exceed benefits. Findings do not differ markedly between men and women; however, deterministic and probabilistic sensitivity analyses reveal meaningful uncertainty about the magnitude of net benefit.