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Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100 mg/kg). Treatments were subcutaneously injected at 1, 6, and 24 h, and then once daily for one week post-injury. 7–8 mice/group were euthanized at 48 h post-injury. 12–16 mice/group underwent behavioral testing at 12 weeks post-injury and MRI at 14 weeks post-injury before being euthanized at 16 weeks post-injury. At 48 h post-injury, markers for activated microglia and astrocytes, as well as …