The current study examined the role of hepatocyte NF-B activation during ischemia/reperfusion injury. Secondly, we evaluated the effects of ischemic hypothermia on NF-B activation and liver injury. C57BL/6 mice underwent 90 minutes of partial hepatic ischemia and up to 8 hours of reperfusion. Body temperature was regulated during the ischemic period between 35-37°C, 33-35°C, 29-33°C, or unregulated, where temperature fell to <29°C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29°C) being highly protected and the normothermic group (35-37°C) displaying the greatest injury. Inflammation, as measured by production of TNF and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in ischemic hypothermia groups. Interestingly, hepatocyte NF-B activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of the IB proteins, IB and IB, was greatest in the normothermic group suggesting an alternate NF-B regulatory mechanism during ischemia/reperfusion injury. Subsequently, we found that NF-B p65 protein was degraded in normothermic versus hypothermic groups and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase, Pin1. The data suggest that NF-B activation in hepatocytes is a protective response during ischemia/reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that the peptidyl-prolyl isomerase, Pin1, promotes NF-B p65 protein stability such that decreased expression of Pin1 during ischemia/reperfusion results in p65 degradation, reduced nuclear translocation of NF-B and enhanced hepatocellular injury.