Tissue factor pathway inhibitor (TFPI) is a novel agent that binds to tissue factor/VII(a) complex and factor-X(a), thereby reducing the effect of tissue factor (TF) on inflammation and the extrinsic pathway of coagulation. We hypothesize that systemic treatment with TFPI may limit ischemia- reperfusion (IR) injury. Our experiment was designed to evaluate the effects of TFPI on IR in the spinal cord. Twenty-three adult New Zealand white rabbits had snare occlusion devices placed circumferentially around the aorta and tunneled to a subcutaneous position. Forty-eight hours later, in the fully awake state, the animals were treated with either TFPI (1 mg/kg bolus followed by a 1-hr infusion of 20 μg/kg/min), or heparin (100 U/kg bolus) followed by a 1-hr infusion of 10 ml/kg/hr of PBS while controls received phosphate buffered saline (20 ml followed by a 1-hr infusion of 10 ml/kg/hr). The infrarenal aorta was occluded for 21 min in all groups via the snare device. Animals were observed for 3 days and neurologic recovery was graded by the Tarlov criteria. Results were evaluated as percent of animals with hindlimb recovery (Tarlov 3 and 4). At 24 hr postocclusion, 88% of the TFPI- treated animals had recovered neurologic function versus only 20% of heparin- treated animals and 10% of the phosphate buffered saline group (P = 0.031 and 0.009, respectively). At 72 hr, 63% of the TFPI animals retained neurologic function versus 20% of heparin-treated animals and 10% of phosphate buffered saline-treated animals (P = 0.032, TFPI versus phosphate buffered saline). The mechanism of action of TFPI is not completely understood, yet this drug may hold promise in the prevention of IR injury of the spinal cord.