BACKGROUND: Pancreas transplantation can successfully restore physiological insulin production, but it comes with a potentially significant morbidity burden. Pancreas grafts are extremely vulnerable to ischemia/reperfusion injury. Investigating technologies that aim to mitigate ischemia/reperfusion injury, such as oxygenated hypothermic machine perfusion (HMPO2) for pancreas preservation and their modes of application, is crucial to inform clinical translation. METHODS: A circulatory death porcine model was used to compare different HMPO2 modes for pancreas preservation. Eighteen porcine pancreases were allocated to 3 experimental groups: static cold storage (SCS), continuous HMPO2, and end-ischemic HMPO2. Normothermic reperfusion (NR) was used for assessment. RESULTS: The ischemic times and wet:dry ratios were comparable among the 3 groups. Perfusate flow increased throughout NR and was highest at the end of NR across all groups, with no significant difference between the groups. Amylase, lipase, lactate dehydrogenase, and cell-free DNA showed no significant differences in the pattern of change among the groups. Red blood cells were present consistently in vessels and islet capillaries at the end of NR in all pancreases. The continuous HMPO2 group showed significantly higher biphasic insulin secretion in response to glucose stimulation (P = 0.01). CONCLUSIONS: Continuous HMPO2 is a superior method for preserving beta-cell function compared with SCS and end-ischemic HMPO2 in a porcine model of circulatory death when assessed by NR with whole blood as a surrogate for transplantation. As end-ischemic HMPO2 is also feasible and potentially superior to SCS, testing its safety would be an excellent first step in translating this technology into clinical practice.