OBJECTIVES:  Colonoscopy is the “gold standard” for colorectal cancer (CRC) screening. However, adherence rates are low and detection is not optimal. Concomitant aspirin chemoprevention is recommended by the US Preventive Task Force, but bleeding complications can be limiting. Variant genotypes in genes of aspirin metabolism can modify CRC and adenoma risk. Genotype-guided aspirin use can identify a targeted average risk population for maximal aspirin benefit, while minimizing adverse events rates compared to the general population. We conducted a cost threshold analysis of genotype-guided aspirin use for primary chemoprevention of CRC in healthy average risk individuals. METHODS:  Our Markov de novo decision analytical model compared genotype-guided aspirin use to no intervention, and to colonoscopy ±general aspirin use. The model incorporated 5 possible health states based on the natural history of CRC progression; no cancer or polyps, adenoma, pre-clinical CRC, CRC, and death. Model probabilities for prevalence and likelihood of developing cancer were estimated using the SEER database and published literature. A microsimulation of 10,000 individuals aged 50-64 years was conducted to estimate the cost-effectiveness of genotype-guided ASA use for CRC prevention from a US payer perspective over a lifetime. RESULTS:  When genetic testing costs were below $63, colonoscopy + genotype-guided aspirin use became the dominant strategy (i.e. lower cost and higher efficacy). When the costs for genetic testing were between $63-283, the costs of using genotype-guided aspirin per quality adjusted life year gained remained below $100,000, a commonly acceptable threshold for reimbursement in many countries. CONCLUSIONS:  Genotype-guided aspirin use with colonoscopy can maximize benefit and decrease adverse event rates for preventing CRC compared to other screening strategies. The economic value of genotype-guided aspirin is dependent on the genetic testing costs.