CpG-oligodeoxynucleotide (ODN), a synthetic analog of bacteria DNA, has attracted attention because it activates cells of an adaptive immune system and the innate immune system. In this study, we investigated whether CpG-ODN has radioprotective effects, when administered after total-body irradiation (TBI). Mice were treated with 50 µg CpG-ODN via intraperitoneal injection (i.p) within 30 min, 24 h and 48 h after TBI. Our results showed that the survival rate was enhanced at various levels of TBI. The calculated dose reduction factor (DRF) was 1.2. Bone marrow cell count and bone marrow histological examination indicated that CpG-ODN minimized the bone marrow damage induced by TBI. The data of the white blood cell (WBC) count, exogenous (CFU-S) and endogenous (endoCFU-S) colony forming unit-spleen count demonstrated that CpG-ODN reduced primitive hematopoietic stem cells damage and reconstituted hematopoiesis after TBI. Thus, we suggested that CpG-ODN had the potential to contribute to the improvement of the survival rate and limitation of myelosuppression induced by TBI.