OBJECTIVES: Accidental exposure to high-dose radiation causes life-threatening acute radiation syndrome, features that include gastrointestinal syndrome (GIS) and hematopoietic syndrome (HS). Administration of vitamin C (VC), a free radical scavenger, has been reported to increase survival of mice in GIS and HS models. The effect of nutritional VC status on radiation injury remains unknown because, unlike humans, mice can synthesize VC. The aim of this study was to investigate the effect of VC insufficiency on acute radiation syndrome using senescence marker protein 30 (SMP30)/gluconolactonase knockout (SMP30-KO) mice. METHODS: SMP30-KO mice, which cannot synthesize VC, were given water with or without sufficient VC supplementation, and were analyzed in GIS and HS models. RESULTS: In the GIS model, in which bone marrow failure is rescued by bone marrow transplantation, VC-insufficient mice had a lower survival rate than VC-sufficient mice. The intestine of VC-insufficient GIS mice showed epithelial cell atrophy, inflammatory cell infiltration, and decreased crypt cell proliferation. We observed rapid VC oxidation after total body irradiation in the intestine of mice supplemented with VC-sufficient water. In the HS model, which was not combined with bone marrow transplantation, there was no difference in survival between VC-insufficient and -sufficient mice. CONCLUSION: The results of this study demonstrated that nutritionally sufficient VC exerts a radioprotective effect against radiation-induced GIS.