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Abstract Circulation of perfluorocarbon (PFC) through corporeal cavities has received interest by virtue of its potential to supplement oxygenation via mechanical ventilation. However, the technology is not mature enough for clinical application, due to the knowledge gaps regarding the limiting factors hampering oxygen transport from PFC to blood. In this paper, we investigate a novel hypothesis that hypothermic peritoneal perfusion of cold oxygenated PFC may improve oxygenation of blood by facilitating the diffusion of oxygen from PFC to blood. Our hypothesis originates from physics-inspired insights that both hypothermia and PFC cooling may increase PFC-to-blood oxygen tension gradient: (i) hypothermia may decrease venous oxygen tension while (ii) cooling PFC may increase oxygen tension therein by increasing its oxygen solubility. Using a physics-based mathematical model capable of simulating oxygen tension responses to mechanical ventilation and peritoneal PFC perfusion under normothermic and hypothermic conditions, we analyzed the effect of hypothermic peritoneal cold PFC perfusion on blood oxygenation. The results predicted that peripheral oxygen saturation may be improved by 5%-10% by peritoneal perfusion of oxygenated 15°C PFC at 32°C body temperature compared with peritoneal perfusion of oxygenated 37.5°C PFC at 37.5°C body temperature. The results also predicted that cooling PFC may play a more meaningful role than hypothermia. Pending the investigation of adverse impact of hypothermia and cold PFC on homeostasis, hypothermic cold PFC perfusion may improve peritoneal oxygenation by facilitating diffusion.