BACKGROUND/AIMS: Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. METHODS: Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. RESULTS: Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). CONCLUSIONS: Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.