Traumatic brain injury (TBI) is a leading cause of death and disability, especially in the younger population. In the acute phase after TBI, patients are more vulnerable to infection, associated with a decreased immune response in vitro. The cause of this immune paralysis is poorly understood. Apart from other neurologic dysfunction, TBI also results in an increase in vagal activity. Recently, the vagus nerve has been demonstrated to exert an anti-inflammatory effect, termed the cholinergic anti-inflammatory pathway. The anti-inflammatory effects of the vagus nerve are mediated by the alpha 7 nicotinic acetylcholine receptor present on macrophages and other cytokine-producing cells. From these observations, we hypothesize that the immune paralysis observed in patients with TBI may, at least in part, result from augmented vagal activity and subsequent sustained effects of the cholinergic anti-inflammatory pathway. This pathway may counteract systemic proinflammation caused by the release of endogenous compounds termed alarmins as a result of tissue trauma. However, sustained activity of this pathway may severely impair the body's ability to combat infection. Since the cholinergic anti-inflammatory pathway can be pharmacologically modulated in humans, it could represent a novel approach to prevent infections in patients with TBI.