The zonal patterns of gene expression in the liver of the rat are not affected by alteration of the afferent hepatic blood source. We investigated whether afferent hepatic blood source or flow rate affects the metabolic capacity of the liver. Using microsurgical techniques, we changed the afferent hepatic blood source to solely arterial blood, solely portal blood or solely caval blood. The transhepatic flow rate was four times higher in arterialized than in cavalized livers. Liver function was tested 2 wk after surgery. Three liver functions were tested (elimination of hepatic iminodiacetic acid from the liver and elimination of galactose and ammoniumbicarbonate from the circulation). Our results show that the afferent hepatic blood flow rate rather than the source of the afferent hepatic blood affects the elimination of the substrates tested. We found that at the physiological flow rate of approximately 15 ml/min and beyond, metabolic function does not depend on the flow of the afferent hepatic blood but that at lower flow rates the flow becomes a major determinant of the metabolic function of the liver. We conclude that the position of the liver within the circulation (i.e. between the gastrointestinal tract and the systemic circulation) is apparently not a prerequisite for adequate metabolic activity, at least for the substrates tested, provided that the liver is sufficiently perfused with blood. (Hepatology 1994;20:1532–1540).