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) impaired splanchnic VO(2) reflects a decrease in metabolic liver function.