Purpose: Benign appearing, biopsy negative gastric ulcers may harbor malignancy. The American Society of Gastrointestinal Endoscopy therefore recommends that such ulcers be followed by endoscopy until complete healing has occurred. Because malignancy in benign appearing gastric ulcers is rare and the sensitivity of initial endoscopy with biopsies is high, it is unclear whether the benefit of endoscopic follow-up is worth the small risks and the cost associated with it. Methods: We developed a cost-effectiveness model to determine whether patients with a benign appearing, biopsy negative gastric ulcer should undergo repeat endoscopy. Using the published literature we determined the probabilities for the prevalence of malignancy in such ulcers, the sensitivity of repeat endoscopy with biopsies to detect cancer, the probability of finding a resectable cancer with and without repeat endoscopy, and the life expectancy associated with resectable and non-resectable gastric cancers. Average direct costs were based on published information (e.g. Medicare CPT codes) and included those associated with repeat upper endoscopy as well as costs related to the treatment of gastric cancer. Utility estimates for quality of life with cancer were also drawn from the literature. Results: In our base-case analysis the strategy of repeat endoscopy cost $93,000 to save one quality adjusted life year (QALY). In sensitivity analysis, the cost-effectiveness ratio of repeat endoscopy falls below $50,000/QALY if the prevalence of malignancy in a benign-appearing, biopsy negative ulcer is more than 1.6% (baseline assumption 0.9%), if the life expectancy benefit associated with finding resectable (as opposed to nonresectable) cancer is more than 7 years (baseline assumption 4.6 years), or if only one follow-up endoscopy with a sensitivity of at least 0.9 (baseline assumption 0.4) is performed. Conclusions: Our model does not support the performance of routine follow-up endoscopy for benign appearing, biopsy negative gastric ulcers when using the conventional cutoff of $50,000/QALY. Improved understanding of the true prevalence and stage of cancer in such lesions would be important to more accurately assess the value of repeat endoscopy.