Hyperoxia following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is associated with worse neurological outcome. This effect is partly mediated through reactive oxygen species (ROS) generation by hyperoxic ventilation during reperfusion. Hydrogen sulfide donor, sodium hydrogen sulfide (NaHS), reduces ROS levels in hyperoxia, which protects cells from oxidative stress. Therefore, this study was designed to test whether NaHS treatment, with and without hyperoxia during CPR, improves neurological outcomes in a mouse model of CA/CPR. Methods: Adult male mice (20–26 g) were subjected to 8 min of CA induced by IV potassium chloride followed by CPR with IV epinephrine, mechanical ventilation, and chest compressions (rate 300/min). Mice were randomly assigned to 4 groups: ventilated with 30% O 2 for 1 h and treated with either normal saline (Normo+NS) or NaHS (3mg/kg i.p. followed by 3mg/kg for 3 days: Normo+NaHS); ventilated with 100% O 2 and either treated with vehicle (Hyper+NS) or NaHS (3mg/kg i.p. followed by 3mg/kg for 3 days: Hyper+NaHS). Four days after CA/CPR, brains were removed for histological evaluation of neurons in the hippocampal CA1 region and the striatum. Results: No difference was found between treatment groups in overall survival, duration of CPR and dose of epinephrine. Histological damages in the hippocampal CA1 region and striatum were reduced in the normoxia groups compared with the hyperoxia groups. Between the hyperoxia groups, NaHS did not alter the outcome in the hippocampal CA1 region or striatum. In contrast, between the normoxia groups, NaHS reduced neuronal damage in the hippocampal CA1 region (Normo+NaHS: 5.9±3.1% vs Normo+NS 20.7±6.3%, P<0.05). Data are expressed as mean±SEM. Conclusions: Combined treatment with NaHS and normoxic ventilation following CA/CPR exerts neuroprotection.