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Introduction: Military members and first responders may, at moment's notice, be asked to assist in incidents that may result in radiation exposure such as Operation Tomadachi in which the U.S. Navy provided significant relief for the Fukushima Daiichi Nuclear Reactor accident in Japan after an earthquake and tsunami in 2011. We are also currently facing potential threats from nuclear power plants in the Ukraine should a power disruption to a nuclear plant interfere with cooling or other safety measures. Exposure to high doses of radiation results in acute radiation syndrome (ARS) characterized by symptoms arising from hematopoietic, gastrointestinal, and neurovascular injuries. Although there are mitigators FDA approved to treat ARS, there are currently no FDA-approved prophylactic medical interventions to help protect persons who may need to respond to radiation emergencies. There is strong evidence that manganese (Mn) has radiation protective efficacy as a promising prophylactic countermeasure., Materials and Methods: All animal procedures were approved by the Institutional Animal Care and Use Committee. Male and female B6D2F1J mice, 10 to 11 weeks old, were used for neurotoxicity studies and temporal effects of Mn. Four groups were evaluated: (1) vehicle injection, (2) dose of 4.5 mg/kg for 3 days, (3) dose of 13.5 mg/kg, and (4) sham. Irradiated mice were exposed to 9.5 Gy whole body Co60 γ-radiation. MRI was performed with a high dose of manganese chloride (MnCl2) (150 mg/kg) to assess the distribution of the MnCl2., Results: The mice have promising survival curves (highest survival-13.5 mg/kg dose over 3 days of MnCl2 at 80% [87% female, 73% male] P = 0.0004). The complete blood count (CBC) results demonstrated a typical hematopoietic response in all of the irradiated groups, followed by mildly accelerated recovery by day 28 in the treated groups. No difference between groups was measured by Rota Rod, DigiGait, and Y-maze. Histologic evaluation of the bone marrow sections in the group given 13.5 mg/kg dose over 3 days had the best return to cellularity at 80%. MRI showed a systemic distribution of MnCl2., Discussion: The preliminary data suggest that a dose of 13.5 mg/kg of MnCl2 given over 3 days prior to exposure of radiation may have a protective benefit while not exhibiting the neurobehavioral problems. A countermeasure that can prophylactically protect emergency personnel entering an area contaminated with high levels of radiation is needed, especially in light that nuclear accidents are a continued global threat. There is a need for a protective agent with easy long-term storage, easy to transport, easy to administer, and low cost. Histologic evaluation supports the promising effect of MnCl2 in protecting tissue, especially the bone marrow using the dose given over 3 days (4.5 mg/kg per day) of MnCl2., Conclusions: Initial experiments show that MnCl2 is a promising safe and effective prophylactic countermeasure against ARS. MRI data support the systemic distribution of MnCl2 which is needed in order to protect multiple tissues in the body. The pathology data in bone marrow and the brain support faster recovery from radiation exposure in the treated animals and decreased organ damage., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)