We previously demonstrated nitrite mediated neuroprotection after asphyxial cardiac arrest (ACA). Reperfusion injury after successful return of spontaneous circulation (ROSC) has been linked to reactive oxygen species generation resulting in loss of cerebral autoregulation with early hyperemia, activation of caspases and delayed neuronal death. Having previously demonstrated nitrite’s cardiac antioxidant effects after cardiac arrest, we hypothesized that a similar mechanism may prevent loss of autoregulation and subsequent caspase activation resulting in neuroprotection. Adult male Sprague–Dawley rats were anesthetized, intubated and catheterized (arterial and venous). An ultrasonic flow probe was placed around the ascending aorta to continuously measure cardiac output (CO) and cerebral cortex blood flow (CBF) was measured using laser speckle analysis through a 5 mm craniotomy. ACA was induced with paralysis and cessation of mechanical ventilation for 8 min prior to manual cardiopulmonary resuscitation with epinephrine and sodium bicarbonate. Animals were randomized 5 min post-ROSC to a 10 min 500 μl infusion of 8 μM nitrite or plasmalyte placebo. Temperature was maintained at 37 °C while heart rate (HR), blood pressure (BP), CO and CBF were measured for one hour and results are reported normalized to baseline values. At 1 h animals were perfused with saline, decapitated and brains homogenized for ascorbate and caspase measurements. In separate experiments without CO/CBF monitoring, animals were survived 24 h before brain homogenization for caspase analysis. Caspase 3/7 activity was measured using a commercial luminescent assay and ascorbate measured using a fluorescent assay with acridine TEMPO. All measurements were normalized to protein content of samples. Comparisons are by repeated measures ANOVA, 1 way ANOVA and Mann–Whitney U tests and mean (physiology, caspase) or median (ascorbate) values are reported below. Animals in both treatment arms had baseline HR, MAP, CO and CBF similar to each other and non-arrested shams and consistent with reported normal values ( Fig. 1 ). Sham physiologic values did not change significantly over 1 h of observation under isoflurane anesthesia. ACA resulted in complete loss of CO and CBF. Ten min after ROSC (5 min after treatment was initiated), CO was diminished (80%) in both treatment groups yet BP was significantly (138%) increased. In placebo animals, this resulted in a significant increase in CBF (187%) compared to nitrite treated animals (136%; p < 0.01). This difference persisted until 20 min after ROSC at which point groups converged. Nitrite treated animals had significantly higher levels of ascorbate (33.09 nmol/mg protein) compared to placebo treated animals (26.17; p = 0.027) 1 h after ROSC. At 24 h, ACA resulted in significant( p < 0.01) increases in caspase-3/7 activity compared to shams (1381 RLU/mg protein) with higher levels in placebo (5383) compared to nitrite (4340) treated animals. Nitrite acts as antioxidant when administered after ROSC blunting subsequent loss of autoregulation and hyperemia, preserving antioxidant reserve and reducing subsequent caspase-3/7 activation. This provides a mechanistic insight into nitrite mediated neuroprotection. Ongoing studies are examining potential subcellular targets for nitrite therapy which may explain these effects. Supported by NINDS K08.