Major trauma provokes a stress response which is mediated, in part, via glucagon, catecholamines, and cortisol. These stress hormones modulate the choice of energy substrate for various tissues. While glucose and fatty acids are considered the preferred fuels, ketone bodies (26/ATP/mole) may be a viable alternative. In this study, we measured the concentrations of acetoacetate and beta-hydroxybutyrate (3-OHB) in the portal as well as systemic circulations of 10 critically injured patients (revised trauma score = 6.8 +/- 0.5, injury severity score = 27 +/- 3) during the first 5 postoperative days. At 6 hr postinjury, 3-OHB was elevated in the portal system (0.34 +/- 0.01 mM) while depressed systemically (0.09 +/- 0.02 mM), indicating that the gut was capable of ketogenesis. In contrast, at 24 hr, 3-OHB rose systemically (0.39 +/- 0.02 mM) while decreasing in portal blood (0.09 +/- 0.01 mM) implying gut ketone consumption. Moreover, the systemic ketone body ratio became elevated at 24 hr, suggesting an enhanced liver energy status. In summary, we believe ketogenesis is stimulated by major trauma. Initially, the gut supports ketone concentration in the systemic circulation, whereas, by 24 hr, the gut becomes a ketone consumer and the liver maintains circulating levels.