Abstract The overarching hypothesis of this proposal is that after ionizing radiation damage in the skin, therapeutics that selectively block the neutrophilic component of the ensuing inflammatory response will have clinical benefit in reducing damage and improving clinical outcomes both acutely and chronically. We further hypothesize that this kind of therapeutic effect can be achieved with agents that inhibit the action of IL-1 that is produced in response to radiation-induced cell death. The rationale for these hypotheses is our recent discovery that the key pathway that is required for neutrophilic inflammation to cell death is IL-1 signaling through IL-1-receptor-1 (IL-1R1)-MyD88 and that blocking this pathway markedly reduces tissue damage after injury. Because this pathway is central to generating neutrophil responses to cell death regardless of the insult, blocking it is likely to have clinical benefit not only for radiation injury but also when that injury is combined with mechanical, chemical or thermal trauma. The goal of this proposal is to test these hypotheses and evaluate the efficacy of IL-1 blocking agents (IL-1Ra and anti-IL-1 antibodies) in mitigating and/or treating post-radiation cutaneous injury in a preclinical mouse model. An attractive feature of this approach is that if it is successful, the development path would be rapid because IL-1Ra agents are already approved for use in man and there is already a substantial body of data showing that IL-1 blockade is safe and well tolerated. Moreover, this therapy would be easy to administer in a mass casualty setting (s.c. injection).