Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2,sp ) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 ± 0.78 L/min) and VO2,sp (3.9 ± 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 ± 0.19 L/min, P < .01) and (2.3 ± 0.7 mmol/min, P< .001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 ± 1.19 L/min) and VO2,sp(3.9 ± 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 ± 0.36 L/min, P< .005; and 2.0 ± 0.6 mmol/min, P< .005). During HVP, HBF increased from 1.67 ± 0.72 to 2.07 ± 1.11 L/min (n=11) in ALF, and from 1.89 ± 1.32 to 2.34 ± 1.54 L/min (n=7) in AOCLD,P < .05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 ± 2.5 vs. 6.6 ± 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 ± 650 vs. 2,020 ± 806 Dyne · s · cm−5 · m2, P< .01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 ± 2.8 to 10.1 ± 2.9 L/min (P< .01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,spincreased by 15% (P< .05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P< .005) and VO2,sp (P< .05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P< .05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2,sp. HVP further increased HBF and DO2,sp but VO2,spwas unchanged, indicating that splanchnic hypoxia was not present.