Daily low-dose aspirin may reduce colon cancer (CRC) incidence and mortality. Recent studies have shown that the preventive effect of aspirin on colon cancer is mainly in the proximal colon. Compared with the effect of colonoscopy in the distal colon, colonoscopy has little or no effect in the proximal colon. The authors evaluated the cost-effectiveness of adding low-dose aspirin to simulated screening with colonoscopy or sigmoidoscopy. The study developed a Markov model that compared 100,000 patients aged 50 years with only 10 years of screening with colonoscopy or sigmoidoscopy with patients who added aspirin to one of the two tests. Screening and aspirin prophylaxis simulations were terminated at age 80. Aspirin spending, aspirin-related complications, and aspirin-related deaths were included. Incremental cost-effectiveness ratios were calculated for the two different strategy groups. Sensitivity and probability analyses were also performed. The results of the study showed that the addition of low-dose aspirin to screening colonoscopy and sigmoidoscopy led to an increase in the prevention of colon cancer deaths: from 68% to 81% and 39% to 69%, respectively. Lifetime aspirin-related mortality was 0.1%. Because of the substantial reduction in colon cancer treatment, the addition of aspirin to colonoscopy and sigmoidoscopy screening was each cost-effective (increased cost-effectiveness ratio:$5,413 per life year saved) and cost-saving ($278 per person). The addition of aspirin was no longer cost-effective when colonoscopy was used to increase the proximal colon cancer prevention rate from baseline to 56-73%. The colonoscopy and sigmoidoscopy plus aspirin strategies were cost-effective in 52% and 94% of the probability analysis scenarios. Thus, when endoscopy is hypothesized to be ineffective in preventing colon cancer, the addition of low-dose aspirin may be an effective and cost-effective strategy, primarily because of its high efficacy in preventing proximal colon cancer.