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Traumatic brain injury can have devastating consequences for patients and extended hospital stays and recovery course. Recent data indicate that the initial insult causes profound changes to the immune system and leads to a pro-inflammatory state. This alteration in homeostasis predisposes patients to an increased risk of infection and underlying autoimmune conditions. Increased emphasis has been placed on understanding this process both in the clinical and preclinical literature. This review highlights the intrinsic inflammatory conditions that can occur within the initial hospital stay, discusses long-term immune consequences, highlights emerging treatment options, and delves into important pathways currently being investigated with preclinical models.