Traumatic brain injury (TBI) activates the NALP1/NLRP1 inflammasome, which is an important component of the early innate inflammatory response to injury. We investigated the influence of therapeutic hypothermia on inflammasome activation after TBI. Adult male Sprague-Dawley rats were subjected to moderate fluid percussion brain injury. Temperature manipulation (33°C or 37°C) was initiated 30 minutes after TBI and maintained for 4 hours. At 4 or 24 hours after TBI, traumatized cortex and hippocampus were prepared for immunoblot or immunohistochemical analysis. In the normothermic groups, caspase-1, caspase-11 and expression of the purinergic receptor P2X7 increased at 24 hours after TBI. Posttraumatic hypothermia lead to decreased expression of these proteins at 24 hours compared with normothermic levels. Immunocytochemical studies showed that posttraumatic hypothermia also decreased caspase-1 staining in cerebral cortical neurons compared with normothermic TBI. Cultured cortical neurons subjected to stretch injury demonstrated significant secretion of caspase-1 into the culture medium and caspase-3 activation, both results reduced by hypothermic treatment. Posttraumatic hypothermia decreases inflammasome signaling in neurons and reduces the innate immune response to TBI at 24 hours after injury. Therapeutic hypothermia may protect the injured central nervous system by targeting the detrimental consequences of the innate immune response to injury.