BACKGROUND AND PURPOSE: Cerebral hypothermia is a known neuroprotectant with promising applications in the treatment of ischemic events. Although systemic cooling is standard in post-cardiac arrest care, the deleterious effects of whole-body cooling have precluded it from translation into a viable treatment option for acute ischemic stroke (AIS). Selective cerebral cooling has been proposed as a method to minimize these risks while granting the neuroprotection of therapeutic hypothermia in AIS. METHODS: In a porcine model (n = 3), the efficacy of selective retrograde cerebral cooling through the internal jugular vein was evaluated in the setting of complete cerebral circulatory arrest. Furthermore, a novel endovascular device and cooling system enabling selective retrograde cerebral cooling were studied in a normothermic perfused cadaver. RESULTS AND CONCLUSION: Neurologic assessment of animals receiving this therapy reflected substantial neuroprotection in animals undergoing both 15 min and 30 min of otherwise catastrophic complete cerebral circulatory arrest. The novel endovascular device and cooling system were validated in human anatomy, demonstrating successful cerebral cooling, and feasibility of this mechanism of selective retrograde cerebral cooling.