Purpose: The widespread use of cross-sectional imaging has led to increased detection of pancreatic cysts. Current management of pancreatic cysts includes endosonographic imaging and cyst fluid analysis; however, the malignant potential of these lesions often remains undetermined. Our study aimed to evaluate whether combining routine cytology and cyst fluid CEA with cyst fluid genetic analyses for allelic imbalance and KRAS mutations can be used to better predict the malignant potential of pancreatic cysts. Methods: Thirty-six patients with pancreatic cysts had EUS-guided fine needle aspiration. Cyst fluid was analyzed for CEA, amylase, KRAS mutations, allelic imbalance, DNA quantity (RedPath Integrated Pathology, Inc), and sent for cytology. Cysts were labeled as serous (CEA <5 ng/ml, amylase <800 U/L, clear aspirate), mucinous (CEA >192 ng/ml, amylase <800 U/L, viscous aspirate), branch duct (BD) IPMN (CEA >192 ng/ml, amylase >800 U/L, viscous aspirate) or indeterminate (CEA 5-192 ng/ml, clear aspirate). Based on KRAS point mutations, allelic imbalance and DNA quantity, cyst fluid genetic analyses were reported as benign, statistically indolent or aggressive. Mean follow-up time was 2.4 years. Results: Of the 36 patients evaluated, 22 were female, 14 male. Based on the above criteria (prior to genetic analysis), there were 6 serous, 8 mucinous, 21 BD-IPMN, and 1 indeterminate cysts (Table). Genetic analysis identified 4 cysts as aggressive and 32 as benign/indolent. Out of four aggressive cysts, one BD-IPMN cyst with adjacent nodule seen on EUS had four LOH mutations, and its surgical pathology revealed adenocarcinoma. The other three aggressive cysts (one BD-IPMN and two mucinous) showed LOH and KRAS mutations, and are pending surgery. Ten out of 32 benign/indolent cases had follow-up imaging, all of which demonstrated no disease progression.Table: No Caption available.Conclusion: When genetic analysis, endosonographic imaging and cytology are all consistent with indolent behavior, close observation in lieu of immediate surgical resection may be appropriate for small (<3 cm) mucinous cysts and BD-IPMNs.