OBJECTIVES: This study aims to assess the cost-effectiveness of aspirin in the primary prevention of cardiovascular events (myocardial infarction (MI) and ischemic stroke (IS)) and colorectal cancer (CRC) in the low-risk general population in the United States (US). METHODS: We developed and validated a Markov model to predict the number of primary events (MI, IS, or CRC) in US Caucasian males using established age-dependent risk data from the literature. Simulations were performed from the US healthcare system perspective using a starting cohort of non-smoking, non-diabetic Caucasian males aged 40 years old with low cardiovascular risk (10-year risk <5%) and normal CRC risks for the aspirin and no-aspirin arms. Annual cycles were simulated until 100 years old. Cost per quality-adjusted life year (QALY) and cost per life year (LY) were used as the primary outcome measures and clinical measures, numbers needed to treat (NNT) and numbers needed to harm (NNH), as secondary outcome measures. A 3% discount rate was applied to both costs and outcomes. Both deterministic and probabilistic sensitivity analyses (PSA) were performed.      RESULTS: Aspirin was found to be the dominant strategy in the base-case analyses. NNT and NNH were 11.1 and 13.6 respectively. One-way sensitivity analyses showed that the findings were highly sensitive to rates of hemorrhagic stroke, utilities of taking pill, aspirin’s effects on cardiovascular events, out-of-hospital MI fatality rates, and CRC risks. PSA showed that when willingness-to-pay (WTP) levels were varied from USD0 to USD100,000 per QALY gained, aspirin is likely to be cost-effective more than 80% of the time.     CONCLUSIONS: Aspirin is likely to be cost-effective as a primary preventive agent. However, the finely balanced NNT and NNH made it premature to recommend aspirin for primary prevention of cardiovascular and CRC events in low-risk Caucasian males. Resources should be channeled towards conducting further studies to generate more precise model inputs.