Traumatic brain injury (TBI) encompasses a broad range of injury severity from mild self-limited injury in the setting of sports to severe injury from motor vehicle crashes, combat injuries, falls, and assault, resulting in disability and death. However, even individuals with similar severity of TBI can sustain greatly different outcomes. The reasons for the diversity in outcomes after TBI are not well understood and likely depend upon a large range of factors related to the patient and to the variable circumstance of the injury itself. Genetic polymorphisms have been considered as potential outcome-modifying factors. Apolipoprotein E (APOE) gene allele status has emerged as an important factor in TBI pathogenesis and as a risk factor for outcomes after TBI. In this chapter, we will introduce TBI and then explore the potential role of apoE isoforms in TBI pathogenesis and outcomes, by summarizing mechanisms and then reviewing effects of APOE allele variants on clinical, imaging, and neurophysiological TBI outcomes and severity.