Background: Although survival rates after asphyxial cardiac arrest (ACA) have improved, survivors face neurological disability from hypoxic ischemic brain injury. Hippocampal CA1 and striatum, which affect cognitive function, are vulnerable. Targeted temperature management (TTM) is the only recommended intervention to improve outcome, yet preclinical studies are lacking on sex-linked behavioral and neurological outcomes after TTM. Hypothesis: TTM produces sex-specific differences in CA1 and striatal associated behavioral and neurological outcomes after ACA. Methods: Adult male and female Sprague-Dawley rats underwent sham or 5-min no-flow ACA. Temperature was controlled for 18h post-ACA at either 37-38°C (normothermia; n=9 males; 14 females) or 36-37°C (TTM; n=9 males; 8 females). Rats underwent neurological deficit scoring (NDS) and behavior testing over 14d. Behavior measures included: coordination, balance, sensorimotor function [acoustic startle response (ASR)] and myoclonus. Neuropathology was examined (cell death [CA1] and microglial infiltration [CA1 and striatum]) at 14d. Results: After ACA, females were less likely to achieve ROSC vs males (76% vs 92%). Females had a longer time to ROSC (p<0.05); but insult severity was similar between sexes based on post-ROSC blood gases. Females had lower NDS vs males at 1-3d post-ACA (p<0.05). ACA females had better coordination, balance, lower ASR, and fewer myoclonic events vs males (p<0.05). ACA females and males had similar amounts of CA1 dead (eosinophilic) and degenerated (fluorojade-B+) neurons and microglia (Iba1). ACA did not impact the number of striatal microglia in either sex vs sham; however more striatal microglia were “activated” than “resting” after ACA. TTM improved survival and NDS in males and females (p<0.05). TTM improved coordination and balance only in males (p<0.05). TTM did not reduce increases in ASR or CA1 death/degeneration. Ongoing work is exploring the effect of TTM on microglial number/activation. Conclusions: Females post-ACA have a lower ROSC but better behavioral outcomes vs males. TTM selectively improved behavioral recovery in males but did not impact CA1 injury. We provide preclinical insight into sex-specific ACA responses, using TTM as a therapy.