It is well established that subjects with liver cirrhosis are insulin resistant, but the contribution of defects in insulin secretion and/or action to glucose intolerance remains unresolved. Healthy individuals and subjects with liver cirrhosis were therefore studied on two occasions. First, an oral glucose tolerance test (OGTT) was performed. Second, insulin secretion was inhibited and glucose infused in a pattern and amount mimicking the systemic delivery rate of glucose following a carbohydrate meal. Insulin was concurrently infused to mimic a healthy postprandial insulin profile. Post-absorptive glucose concentrations were equal (5.36±0.12 vs. 5.40±0.25 mmol/l; P=0.89) despite higher insulin (P<0.01), C-peptide (P<0.01), and FFA (P=0.05) concentrations in the cirrhotic than in the control subjects. Endogenous glucose release (EGR) (11.50±0.50 vs. 11.73±1.00 µmol/kg/min; P=0.84) and the contribution of gluconeogenesis to EGR were unaltered by cirrhosis (6.60±0.47 vs. 6.28±0.64 µmol/kg/min; P=0.70). A minimal model recently developed for the OGTT demonstrated an impaired insulin sensitivity index (P<0.05), while the -cell responsitivity to glucose was unaltered (P=0.72). During the prandial glucose and insulin infusions, the integrated glycemic response was greater in the cirrhotic than in the control subjects (P<0.05). EGR decreased promptly and comparably in both groups, but glucose disappearance was insufficient at the prevailing glucose concentration (P<0.05). Moreover, identical rates of [3-³H] glucose infusion produced higher tracer concentrations in the cirrhotic than in the control subjects (P<0.05) implying a defect in glucose uptake. In conclusion, carbohydrate intolerance in liver cirrhosis is determined by both insulin resistance and the ability of glucose to stimulate insulin secretion. During the prandial glucose and insulin concentrations EGR suppression was unaltered, but glucose uptake was impaired, which demonstrates that intolerance can be ascribed to a defect in glucose uptake rather than to abnormalities in glucose production or -cell function. While insulin secretion ameliorates glucose intolerance impaired glucose uptake during physiologic glucose and insulin concentrations produces marked and sustained hyperglycemia despite concurrent abnormalities in glucose production or insulin secretion.