Radiation injury to skin poses substantial morbidity risks in the curative treatment of cancers and is also of concern in the context of radiological attack or nuclear accident scenarios. Late effects can be severe and are frequently characterized by subcutaneous fibrosis and morbidity. These experiments presented here assess the potential of MW01-2-151SRM (MW-151), a novel small-molecule inhibitor of microglial activation and associated proinflammatory cytokine/chemokine production, as a mitigator of radiation-induced skin injury. Groups of C57BL/6 mice received focal irradiation of the right hind leg at a dose of 30 Gy. Therapy was initiated either on day 3, day 7 or day 14 postirradiation and maintained subsequently for 21 days by intraperitoneal injections administered three times per week. The primary end point was skin injury, which was assessed three times a week for at least 60 days postirradiation and scored using a semi-quantitative scale. Secondary end points measured at selected times included histology (primarily H&E) and immunofluorescence labeling of various macrophage (F4-80) and inflammatory (TGF-β, TNF-α, MMP9) markers. Relative to untreated controls, mitigation of radiation-induced skin injury in mice receiving MW-151 was highly dependent on the timing of therapy initiation. Initiation on day 3 postirradiation had no discernable effect, whereas mitigating effects were maximal following initiation on day 7 and present to a lesser degree following initiation on day 14. The response to MW-151 therapy in individual animals was essentially all-or-none and the relative benefits associated with the timing of therapy initiation primarily reflected differences in the number of responders. These data support the hypothesis that proinflammatory cytokines/chemokines play complex roles in orchestrating the response to radiation-induced skin injury and suggest that there is a critical period during which they initiate the pathogenesis resulting in late effects.