To characterize causes of death in the operating room (OR) following major trauma, a retrospective review of admissions to eight academic trauma centers was conducted to define the etiology of death and challenges for improvement in outcome. Five hundred thirty seven OR deaths of 72,151 admissions were reviewed for mechanism of injury, physiologic findings, resuscitation, patterns of injury, surgical procedures, cause of death, and preventability. Blunt injuries accounted for 61% of all injuries, gunshot wounds (GSW) accounted for 74% of penetrating injuries. Sixty two percent of all patients arrived in shock. Average blood pressure (BP) was 52 mm Hg at the scene and 60 mm Hg on admission, with the period of shock > 10 minutes in 74%. Only 56% were resuscitated to a BP > 90 mm Hg before surgery. Average time to the OR was 30.1 minutes and mean best postresuscitation pH was 7.18. Mean best OR temperature was 32.2 degrees C. Recurrent injury patterns judged as the primary cause of patient death included head/neck injury (16.4%), chest injury (27.4%), and abdominal injury (53.4%). Actual cause of death was bleeding (82%), cerebral herniation (14.5%), and air emboli (2.2%). A different strategy for improved outcome was identified in 54 patients with the following conclusions: (1) delayed transfer to the OR remains a problem with significant BP deterioration during delay, particularly following interfacility transfer; (2) staged injury isolation and repair to allow better resuscitation and warming may lead to improved results; (3) combined thoraco-abdominal injuries, particularly with thoracic aortic disruption, often require a different sequence of management; (4) aggressive evaluation of retroperitoneal hematomas is essential; (5) OR management of severe liver injuries remains a technical challenge with better endpoints for packing needed; and (6) resuscitative thoracotomy applied to OR patients in extremis from exsanguination offers little.