BACKGROUND: Colon cancer screening with colonoscopy is an accepted strategy; however, there are limited data regarding the cost-effectiveness of screening for upper GI cancers (esophageal adenocarcinoma with its premalignant precursor Barrett's esophagus, esophageal squamous cell cancer, gastric adenocarcinoma) in the United States. OBJECTIVE: To evaluate the cost-effectiveness of screening the general population for upper GI cancers by performing an upper endoscopy at the time of screening colonoscopy. DESIGN: Decision analysis. SETTING: Third-party-payer perspective with a time horizon of 30 years or until death. PATIENTS: This study involved 50-year-old patients already undergoing screening colonoscopy. INTERVENTION: Comparison of two strategies: performing and not performing a screening upper endoscopy at the time of screening colonoscopy. MAIN OUTCOME MEASUREMENTS: Incremental cost-effectiveness ratio (ICER). RESULTS: One-time screening for the general population at the age of 50 for upper GI cancers required $115,664 per quality-adjusted life year (QALY) compared with no screening or surveillance. A strategy of screening and surveillance for Barrett's esophagus required only $95,559 per QALY saved. In 1-way sensitivity analyses, the prevalence rates of esophageal adenocarcinoma, esophageal squamous cell cancer, or gastric adenocarcinoma would have to increase by 654%, 1948%, and 337%, respectively, to generate an ICER of less than $50,000 per QALY. LIMITATIONS: Omission of premalignant conditions for squamous cell cancer and gastric adenocarcinoma. CONCLUSION: The ICER for screening the general population for upper GI cancers with endoscopy remains high, despite accounting for reduced endoscopy costs and the combined benefits of detecting early esophageal adenocarcinoma, esophageal squamous cell cancer, and gastric adenocarcinoma. However, the ICER compares favorably with commonly performed screening strategies for other cancers.