An increasing number of preclinical and clinical studies show that high-dose i. v. vitamin C can mitigate systemic, cerebral and myocardial ischemia/reperfusion injury. Vitamin C administration has been associated with reduced oxidative stress, myocardial injury and arrhythmias and improved microcirculation, neurological outcome and survival, although not all studies showed benefit. Because of the common pathophysiological pathway of sepsis and ischemia/reperfusion injury, the potential role of vitamin C for ischemia/reperfusion injury is further supported by the results of preliminary sepsis studies, showing earlier recovery from organ failure and higher survival rates. Therefore, early, high-dose i. v. vitamin C is a promising therapeutic intervention after cardiac arrest to diminish the systemic ischemia/reperfusion injury due to overwhelming oxidative stress. The supportive evidence from preclinical and clinical studies is too large to continue considering early high-dose i. v. vitamin C as alternative medicine. An RCT is urgently required to provide definitive proof as to whether this cheap and safe therapy does indeed improve outcome.