The purpose of this study was to elucidate the role of α-tocopherol succinate (α-TS) in protecting mice from gastrointestinal syndrome induced by total-body irradiation. CD2F1 mice were injected subcutaneously with 400 mg/kg of α-TS and exposed to different doses of (60)Co γ radiation, and 30-day survival was monitored. Jejunum sections were analyzed for crypts and villi, PUMA (p53 upregulated modulator of apoptosis), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling - TUNEL). The crypt regeneration in irradiated mice was evaluated by 5-bromo-2-deoxyuridine (BrdU). Bacterial translocation from gut to heart, spleen and liver in α-TS-treated and irradiated mice was evaluated by bacterial culture on sheep blood agar, colistin-nalidixic acid, and xylose-lysine-desoxycholate medium. Our results demonstrate that α-TS enhanced survival in a significant number of mice irradiated with 9.5, 10, 11 and 11.5 Gy (60)Co γ radiation when administered 24 h before radiation exposure. α-TS also protected the intestinal tissue of irradiated mice in terms of crypt and villus number, villus length and mitotic figures. TS treatment decreased the number of TUNEL- and PUMA-positive cells and increased the number of BrdU-positive cells in jejunum compared to vehicle-treated mice. Further, α-TS inhibited gut bacterial translocation to the heart, spleen and liver in irradiated mice. Our data suggest that α-TS protects mice from radiation-induced gastrointestinal damage by inhibiting apoptosis, promoting regeneration of crypt cells, and inhibiting translocation of gut bacteria.