Combat-related injuries to the central nervous system (CNS) are of critical importance because of potential catastrophic outcomes. Although the overall infection rate of combat-related CNS injuries is between 5% and 10%, the development of an infectious complication is associated with a very high morbidity and mortality. This review focuses on the prevention of infections related to injuries to the brain or the spinal cord and provides evidence-based medicine recommendations from military and civilian data for the prevention of infection from combat-related CNS injuries. Prevention strategies emphasize the importance of expert evaluation and management by a neurosurgeon as expeditiously as possible. Areas of focus include elimination of cerebrospinal fluid leaks, wound coverage, postinjury antimicrobial therapy, irrigation, and debridement. Given that these recommendations are not supported by randomized control trials or adequate cohort studies in a military population, further efforts are needed to determine the best treatment strategies. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma.