Mild traumatic brain injury resulting from exposure to an explosive blast is associated with significant neurobehavioral outcomes in soldiers. Little is known about the neuropathologic consequences of such an insult to the human brain. This study is an attempt to understand the effects of an explosive blast in a large animal gyrencephalic brain blast injury model. Anesthetized Yorkshire swine were exposed to measured explosive blast levels in 3 operationally relevant scenarios: simulated free field (blast tube), high-mobility multipurpose wheeled vehicle surrogate, and building (4-walled structure). Histologic changes in exposed animals up to 2 weeks after blast were compared to a group of naive and sham controls. The overall pathologic changes in all 3 blast scenarios were limited, with very little neuronal injury, fiber tract demyelination, or intracranial hemorrhage observed. However, there were 2 distinct neuropathologic changes observed: increased astrocyte activation and proliferation and periventricular axonal injury detected with β-amyloid precursor protein immunohistochemistry. We postulate that the increased astrogliosis observed may have a longer-term potential for the exacerbation of brain injury and that the pattern of periventricular axonal injury may be related to a potential for cognitive and mood disorders.