Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and typically involves a robust immune response. Although a great deal of preclinical research has been conducted to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI, including how extracranial factors can influence the aftermath of TBI. For example, most preclinical studies have utilized isolated TBI models in young adult males, while clinical trials typically involve highly heterogeneous patient populations (e.g., different mechanisms of injury, a range of ages, presence of polytrauma or infection). This paper will review the current, albeit limited literature related to how TBI is affected by common concomitant immunological stressors. In particular, discussion will focus on whether extracranial trauma (i.e., polytrauma), infection, and age/immunosenescence can influence TBI pathophysiology, and thereby may result in a different brain injury than what would have occurred in an isolated TBI. It is concluded that these immunological stressors are all likely to be TBI modifiers that should be further studied and could impact translational treatment strategies.