Untreated flow-dependent oxygen consumption (Vo2) has recently been implicated as an unrecognized risk factor for multiple organ failure (MOF). We therefore prospectively studied 39 severely injured patients with known risk factors for multiple organ failure who were subjected to an established resuscitation protocol aimed at maximizing oxygen delivery (Do2 > 600 mL/min·m2) to attain a Vo2 goal of >150 mL/min·m2. Fifteen (38%) of these high risk patients did not meet this Vo2 goal by 12 hours. These nonresponding patients had significantly elevated lactate levels, suggesting defective aerobic metabolism. Of note, this blunted Vo2 response despite maximal efforts to enhance peripheral oxygen availability predicted MOF. These data serve to reemphasize the importance of the initial shock insult in causing or priming the host for the development of late MOF.