BACKGROUND: The importance of early and aggressive management of trauma- related coagulopathy remains poorly understood. We hypothesized that a trauma exsanguination protocol (TEP) that systematically provides specified numbers and types of blood components immediately upon initiation of resuscitation would improve survival and reduce overall blood product consumption among the most severely injured patients. METHODS: We recently implemented a TEP, which involves the immediate and continued release of blood products from the blood bank in a predefined ratio of 10 units of packed red blood cells (PRBC) to 4 units of fresh frozen plasma to 2 units of platelets. All TEP activations from February 1, 2006 to July 31, 2007 were retrospectively evaluated. A comparison cohort (pre-TEP) was selected from all trauma admissions between August 1, 2004 and January 31, 2006 that (1) underwent immediate surgery by the trauma team and (2) received greater than 10 units of PRBC in the first 24 hours. Multivariable analysis was performed to compare mortality and overall blood product consumption between the two groups. RESULTS: Two hundred eleven patients met inclusion criteria (117 pre-TEP, 94 TEP). Age, sex, and Injury Severity Score were similar between the groups, whereas physiologic severity (by weighted Revised Trauma Score) and predicted survival (by trauma-related Injury Severity Score, TRISS) were worse in the TEP group (p values of 0.037 and 0.028, respectively). After controlling for age, sex, mechanism of injury, TRISS and 24-hour blood product usage, there was a 74% reduction in the odds of mortality among patients in the TEP group (p = 0.001). Overall blood product consumption adjusted for age, sex, mechanism of injury, and TRISS was also significantly reduced in the TEP group (p = 0.015). CONCLUSIONS: We have demonstrated that an exsanguination protocol, delivered in an aggressive and predefined manner, significantly reduces the odds of mortality as well as overall blood product consumption.