Objective: This study aimed to clarify whether therapeutic hypothermia protects against cerebral edema following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in a porcine model via regulating the angiopoietin-Tie-2 ligand-receptor system. Methods: Male pigs were randomized into the therapeutic hypothermia group, the normothermia group or the sham control group. CA was induced in pigs by untreated ventricular fibrillation for 8 min. Brain edema was determined by measuring the cerebral cortical water content at 24 h after the return of spontaneous circulation (ROSC). The serum levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (Tie-2), and S100B were measured using enzyme immunoassay kits at 0.5, 6, 12 and 24 h after ROSC. The levels of the Ang-1, Ang-2, phosphorylated Tie-2 and Tie-2 proteins in the cerebral cortex at 24 h after ROSC were determined by Western blotting. Results: Therapeutic hypothermia lessened brain cortex edema, alleviated histopathology injury, and improved neurologic outcomes at 24 h after ROSC. Therapeutic hypothermia inhibited the CA-and CPR-induced increases in serum Ang-2 protein expression and the Ang-2/Ang-1 ratio and attenuated the decrease in serum Ang-1 expression. Therapeutic hypothermia also increased the protein expression of Ang-1 and the phosphorylated Tie2/Tie-2 ratio and inhibited the expression of Ang-2 in the cerebral cortex at 24 h after ROSC. Conclusions: Based on our experiment, therapeutic hypothermia decreased cerebral edema after CA, which may be, at least in part, related to its ability to modulate the expression of components of the Ang-Tie-2 system. (C) 2017 Elsevier Inc. All rights reserved.