The aim of this study is to (1) characterize the impact of orthotopic liver transplantation (OLT) on splanchnic and systemic oxygen uptake (VO 2 ) in patients with liver cirrhosis, and (2) investigate possible influencing factors, as well as metabolic consequences, of reduced splanchnic VO 2 in patients with cirrhosis. Therefore, we measured systemic VO 2 (indirect calorimetry), portal pressure (hepatic venous pressure gradient), hepatic blood flow (HBF; primed continuous infusion of indocyanine green), and hepatic turnover (arteriohepatic venous concentration differences multiplied by HBF) of oxygen, glucose, free fatty acids (FFAs), and aromatic amino acids (AAAs) in 52 patients with advanced cirrhosis and 16 patients with a clinically stable long-term course after OLT. Systemic VO 2 was significantly increased in patients with cirrhosis (261 ؎ 7 mL/min) and normalized after OLT (216 ؎ 8 mL/min; P < .001). Arterial and hepatic venous oxygen saturation and splanchnic oxygen extraction (in percent) were not different between patients with cirrhosis and after OLT. Splanchnic VO 2 was decreased in patients with cirrhosis (41 ؎ 3 mL/min, representing 16% ؎ 1% of systemic VO 2 ) and normalized after OLT (69 ؎ 6 mL/min; P < .001, representing 32% ؎ 3% of systemic VO 2 ; P < .001). In patients with cirrhosis, a decrease in HBF was associated with decreased splanchnic VO 2 (r ؍ 0.74; P < .001). Conversely, decreased splanchnic VO 2 reflected a decrease in hepatic glucose production (r ؍ 0.34; P ؍ .01) and hepatic extraction of FFAs (r ؍ 0.40; P < .01) and AAAs (r ؍ 0.30; P < .05). These results show that (1) splanchnic and systemic VO 2 normalize after OLT, indicating correction of hepatic and extrahepatic metabolic derangements; (2) in cirrhosis, HBF becomes limiting for hepatic oxygen supply; and (3) T he high metabolic activity of the liver demands a sufficient oxygen supply. In healthy controls at rest in the postabsorptive state, hepatic oxygen uptake (VO 2 ) was determined to be approximately 55 mL/min, representing approximately 25% of whole-body VO 2 , whereas splanchnic VO 2 was approximately 70 mL/min. 1,2 A normal organ takes up oxygen in approximately equal parts from the portal vein and hepatic artery; the special anatomy of the normal liver does not represent a major diffusion barrier for oxygen. 1 Under normal conditions, hepatic oxygen extraction is less than 40% of supply. Importantly, in healthy controls, there is no dependence of liver blood flow on an increased hepatic oxygen requirement; an increased hepatic need for oxygen is met by increasing the extraction percentage from blood. 1,3 In cirrhosis, hepatic and splanchnic VO 2 are decreased. 4,5 The cirrhotic liver cannot meet an increased oxygen need by increasing oxygen extraction from the blood. 3,6 Therefore, in the diseased liver, hepatic blood flow (HBF)-dependent oxygen supply may become limiting for the metabolic capacity of the liver. 1,[7][8][9] Interestingly, in a large proportion of patients with liver cirrhosis, resting ener...