BACKGROUND & AIMS: Screening for Barrett's esophagus with conventional esophagoduodenoscopy (EGD) is recommended to decrease mortality from esophageal adenocarcinoma. Esophageal capsule endoscopy (ECE) has recently been shown to be accurate in detecting Barrett's esophagus. We aimed to compare the cost-effectiveness of screening by ECE with screening by EGD. METHODS: A Markov model of 50-year-old white men with symptoms of gastroesophageal reflux was constructed to compare screening modalities. The model incorporated direct medical costs and indirect costs of lost productivity and followed the patients until age 80 years or death. Outcomes were analyzed from the societal perspective. RESULTS: EGD screening prevented 60% of cancer deaths at a cost of $11,254 per quality-adjusted life year gained compared with no screening. ECE prevented 53% of cancer deaths and provided 9 fewer quality-adjusted days at greater cost than EGD. If society were only willing to pay $50,000 per quality-adjusted life year gained, then capsule screening would be preferred if the income of the patient and driver were each greater than $280,682. Otherwise, the findings were robust to all sensitivity analyses. CONCLUSIONS: Screening for Barrett's esophagus with either EGD or ECE results in similar outcomes, but EGD is the preferred strategy. Both strategies appear cost-effective, and the model does not take into account patient preferences for screening modality or adherence.