Data suggest that aspirin, statins, or a combination of the two drugs may lower the progression of Barrett's esophagus to esophageal adenocarcinoma. However, aspirin is associated with potential complications such as gastrointestinal bleeding and hemorrhagic stroke, and statins are associated with myopathy. We developed a simulation disease model to study the effectiveness and cost effectiveness of aspirin and statin chemoprevention against esophageal adenocarcinoma. A decision analytic Markov model was constructed to compare four strategies for Barrett's esophagus management; all regimens included standard endoscopic surveillance regimens: (i) endoscopic surveillance alone, (ii) aspirin therapy, (iii) statin therapy, and (iv) combination therapy of aspirin and statin. Endpoints evaluated were life expectancy, quality-adjusted life years (QALY), costs, and incremental cost-effectiveness ratios (ICER). Sensitivity analysis was performed to determine the impact of model input uncertainty on results. Assuming an annual progression rate of 0.33% per year from Barrett's esophagus to esophageal adenocarcinoma, aspirin therapy was more effective and cost less than (dominated) endoscopic surveillance alone. When combination therapy was compared with aspirin therapy, the ICER was $158,000/QALY, which was above our willingness-to-pay threshold of $100,000/QALY. Statin therapy was dominated by combination therapy. When higher annual cancer progression rates were assumed in the model (0.5% per year), combination therapy was cost-effective compared with aspirin therapy, producing an ICER of $96,000/QALY. In conclusion, aspirin chemoprevention was both more effective and cost less than endoscopic surveillance alone. Combination therapy using both aspirin and statin is expensive but could be cost-effective in patients at higher risk of progression to esophageal adenocarcinoma.