Background: The optimal surveillance strategy for pancreatic cysts, which occur in up to 20% of the adult population, is ill defined. Although risk of malignant degeneration of these cysts is low, pancreatic cancer mortality remains high. Two cyst surveillance guidelines, one proposed by an international consensus group (Fukuoka) and the other by the American Gastroenterological Association (AGA), are accepted standards. Both rely on radiographic and endoscopic ultrasonographic imaging. They differ in indications for, and intervals between, imaging tests, with the Fukuoka guideline advocating more intensive imaging. Clinical guidelines that provide discordant recommendations may undercut the quality and/or value of care, and have implications for societal health care costs. The primary objective of this prospective trial is to compare the clinical effectiveness and associated resource utilization of the Fukuoka and AGA guidelines for pancreatic cyst surveillance. Secondary objectives include a comparison of resource utilization and patient reported outcomes. We are also collecting and banking radiomics data and biospecimens to identify novel methods that might improve cancer risk stratification. Methods: 4606 asymptomatic patients with newly identified pancreatic cysts ≥1cm in diameter are being randomized 1:1 to high intensity (Fukuoka) or low intensity (AGA) surveillance. The primary endpoint is a composite of any pancreatic cancer without surgery, unresectable pancreatic cancer or cancer > T1a, N0 at surgery, and benign disease at surgery. This sample size will provide 90% power to identify a 30% relative difference in the primary outcome at 5 years between the two study arms. Study duration is 8 years in total, allowing for 2 years of cohort enrollment, 5 years of prospective follow-up, and six months reserved for study initiation and close out. Study participants must be ≥ 50 years and ≤ 75 years with an ECOG Performance Status 0-1 at baseline. Participants must have received a CT or MRI within 6 months of registration that identifies a new ≥1 cm pancreatic cyst. Patients with a prior diagnosis of a pancreatic cyst, pancreatic malignancy or a history of pancreatic resection are not eligible. Additional exclusion criteria include a history of acute or chronic pancreatitis, a family history of pancreatic adenocarcinoma in 1 or more first degree relatives, imaging findings or clinical signs that would prompt immediate surgical consideration (enhancing mural nodule, solid component in cyst, pancreatic duct > 10mm, cyst causing obstructive jaundice), a comorbid illness that precludes pancreatic cyst resection, pregnancy or current participation in an established surveillance program. As of February 4, 2021, thirty three (33) participants have been enrolled from two hundred (200) potential sites. Clinical trial information: NCT04239573.