Background: Clinical and cohort studies have shown that low-dose aspirin and calcium are effective lowrisk strategies for primary prevention of colorectal cancer (CRC).Wecompared the cost-effectiveness of aspirin and calcium chemoprevention used with colonoscopy for primary prevention of CRCs. Methods: Markov chain Monte Carlo simulations for a population of 100,000 persons, with a colonoscopy compliance rate of 50%, were used for the analysis. If adenomas were detected, colonoscopy was repeated every 4 years until no adenomas were evident. Data sources included adenoma transition rates, initial adenoma and CRC incidences, and treatment complication rates from existing literature. Age-adjusted U.S. standard population mortality rates were used and costs were from Medicare reimbursement data. The target population was U.S. adults, undergoing CRC screening from ages 50 to 75 years. Results: Outcomes included incremental cost-effectiveness ratios (ICER), life-years saved (LYS), and cancerfree years saved (CFYS). The ICER per LYS for colonoscopy alone dominated compared with no screening. Compared with colonoscopy alone, colonoscopies with aspirin (ICER $12,950/LYS) or calcium (ICER $13,041/LYS) were the next most cost-effective strategies. ICERs per CFYS were $3,061 and $2,317 for aspirin and calcium, respectively, when added to colonoscopy. Sensitivity analyses indicated that initial prevalence of adenomas was a main determinant of prevention cost-effectiveness. Conclusion: Low-dose aspirin or calcium supplementation may be beneficial when added to colonoscopy, for optimum CRC prevention, at small incremental costs. Impact: Cost-effectiveness analyses suggest that aspirin and calcium in combination with colonoscopies are cost-effective for CRC prevention in average-risk populations.