Intraperitoneal injection of a replication-deficient adenovirus containing the HST-1 (FGF-4) gene (Adex1HST-1) increased peripheral platelet counts in mice, and also effectively prevented experimentally induced thrombocytopenia. Here, we report the therapeutic potential of Adex1HST-1 on severely injured mice after exposure to otherwise lethal irradiation. Eighteen out of 20 mice that received Adex1HST-1 prior to gamma-irradiation (9 Gy) survived, while all the 20 mice with prior administration of control adenoviruses died after irradiation (P<0.0001). Hematological and histopathological analyses revealed that Adex1HST-1 acts as a potent protector against lethal irradiation, which causes injury of intestinal tract as well as myelosuppression in the bone marrow and spleen. These data demonstrate that the protective effects of administration of Adex1HST-1 against irradiation are superior to any other protective effects of cytokines against a lethal dose of irradiation, and that the pre-administration of Adex1HST-1 may be useful for lessening the side effects of currently used chemo- and radio-therapy against cancer.