BACKGROUND: Hydrogen is a potent antioxidant agent that can easily be administered by inhalation. The aim of the study was to evaluate whether hydrogen protects the endothelial glycocalyx layer after successful cardiopulmonary resuscitation (CPR). METHODS: Fourteen anesthetized pigs underwent CPR after induced ventricular fibrillation. During CPR and return of spontaneous circulation, 2% hydrogen gas was administered to seven pigs (hydrogen group) and seven constituted a control group. Biochemistry and sublingual microcirculation were assessed at baseline, during CPR, at the 15th, 30th, 60th, 120th minute. RESULTS: All seven subjects from the hydrogen group and six subjects in the control group were successfully resuscitated after 6–10 minutes. At baseline, there were no statistically significant differences in examined variables. After the CPR, blood pH, base excess, and lactate showed significantly smaller deterioration in the hydrogen group than in the control group. By contrast, plasma syndecan-1 and the measured variables obtained via sublingual microcirculation did not change after the CPR; and were virtually identical between the two groups. CONCLUSION: In pigs, hydrogen gas inhalation during CPR and post-resuscitation care was associated with less pronounced metabolic acidosis compared to controls. However, we could not find evidence of injury to the endothelium or glycocalyx in any studied groups.