OBJECTIVES: To estimate the costs and benefits of diagnosis strategies using DNA testing for mucinous pancreatic cysts (MPCs). METHODS: A decision tree was constructed that compared three diagnostic strategies for pancreatic cysts: 1) endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with cyst fluid testing for carcinoembryonic antigen (CEA); 2) strategy 1+DNA testing if insufficient fluid for a CEA; 3) strategy 2+DNA testing if the CEA is indeterminate. Probabilities of insufficient fluid, positive, negative, and, indeterminate CEA results, and positive DNA results given insufficient fluid or indeterminate results were calculated from a database of 286 patients receiving EUS-FNA and the DNA test. Patients who had pancreatic cysts and were not indicated for surgery by cytology alone were divided into the four possible CEA-result groups using criteria that specifies <5 is negative, and >192 positive. The DNA test was considered positive if any of three components (DNA quantity, K-ras mutation, and multiple allelic imbalance mutations) were positive. RESULTS: Based on the database, 38.5% had insufficient fluid for CEA. Of CEAs, 50% were positive, 21.6% negative, and 28.4% indeterminate. Probabilities of a positive DNA test were 6.9% in patients with negative, 36.8% with indeterminate, and 55.2% with positive CEAs, and 35.7% in patients with insufficient fluid. Including costs of cytology but not the EUS-FNA, costs were $381, $1575, and $2642 per patient for the three strategies. Assuming the DNA is not specific enough for a negative diagnosis, the costs per MPC diagnosis are $866, $2716, and $4128 with 44%, 58%, and 64% being diagnosed. Positive diagnosis results in annual follow–up with potential for surgical resection. CONCLUSIONS: Scenarios in which negative DNA tests forego or reduce frequency of follow-up with minimal increase in cancer risk are potentially cost-effective. However, if positive and indeterminate diagnoses are treated similarly, the DNA test cost cannot be justified.