The aim of this study is to understand several adult trials that have investigated the potential benefit of high-dose vitamin C therapy in critically ill patients. In pediatric patients, little is known on the efficacy, safety, and risk of high-dose vitamin C therapy. We aimed to review the efficacy and potential harm associated with high-dose vitamin C treatment. We searched MEDLINE, EMBASE, Cochrane Library, and National Institute of Health Clinical Trials Register. We included studies in neonatal and pediatric patients who received IV or intra-arterial high-dose vitamin C (ascorbic acid) defined as greater than or equal to 75 mg/kg/d. Two independent investigators screened articles and extracted data. We found 1,364 articles, assessed 193 full texts for eligibility, and identified 12 eligible studies. These studies included 855 patients, with 194 receiving high-dose vitamin C. The age of patients who received high-dose vitamin C ranged from 2 hours after delivery to 8.4 years (median 2.4 yr), and the vitamin C dose ranged from 100 to 1,500 mg/kg/d (median 260.5 mg/kg/d). Four studies were double-blind randomized controlled trials, and no clinical efficacy outcome was reported in favor of or against vitamin C. Furthermore, no adverse event or signal of harm was reported with high-dose vitamin C. In 12 studies with 194 children treated with parenteral high-dose vitamin C, there was no evidence of clinical efficacy or inferior clinical outcomes in double-blind randomized controlled trials, and no reported harmful effects. These findings justify further investigations of this treatment in children.