Background: In previous piglet experiments of profound asphyxia and cardiac arrest, recovery was similar when 21 and 100% oxygen were used for positive pressure ventilation (PPV). There was no consistent reduction in inflammation and oxidative stress in piglets ventilated with 21 or 100% oxygen. Objectives: We aimed to investigate hypoxic resuscitation, i.e., PPV with 18% oxygen, in profoundly asphyxiated piglets with cardiac arrest. We hypothesized that resuscitation with 18% oxygen would result in less inflammation and oxidative stress compared to 21 or 100% oxygen. Method: Twenty-four piglets were exposed to 30 min of normocapnic hypoxia followed by asphyxia until asystole. The piglets were randomized to PPV with 18% oxygen (n = 8), 21% oxygen (n = 8), or 100% oxygen (n = 8), and resuscitated with chest compressions and intravenous epinephrine. Return of spontaneous circulation (ROSC) was defined as an unassisted heart rate ≥100 bpm for 15 s. Lactate, GSH (total glutathione), GSSG (oxidized glutathione), and GSSG/GSH ratio were measured in myocardial and frontoparietal cortex homogenates. Interleukin (IL)-8, IL-6, IL-1β and tumor necrosis factor α were measured in frontoparietal cortex homogenates. Results: There was no difference in time to ROSC or inflammation and oxidative stress in the 3 oxygen groups. Conclusions: Resuscitation with 18% oxygen did not result in differences in inflammation and oxidative stress when compared to 21 or 100% oxygen.