Cirrhosis of the liver is frequently associated with carbohydrate intolerance but it is unknown whether this intolerance is due to increased hepatic glucose production (HGP), decreased glucose utilization, or both. HGP and the MCR of glucose [(MCR)G] were measured at steady state, basally and during an infusion of insulin (25 mU/kg x h) and glucose (11 mumol/kg x min), in 11 cirrhotics and 8 controls using the technique of a primed constant infusion of [3H]3-glucose. HGP was also estimated at nonsteady state during an infusion of glucagon (8 ng/kg x min). Basal HGP was significantly lower in cirrhotics compared to controls (10.2 +/- 0.6 vs. 13.2 +/- 0.6 mumol/kg x min; P < 0.0025). During the insulin/glucose infusion, HGP was suppressed to the same degree in both groups [in controls by 83% (13.2 +/- 0.6 to 2.2 +/- 0.8 mumol/kg x min) and in cirrhotics by 87% (10.2 +/- 0.6 to 1.3 +/- 0.4 mumol/kg x min)]. After the glucagon infusion, HGP rose by a similar degree in cirrhotics and controls. In contrast, basal (MCR)G was significantly lower in the nondiabetic cirrhotics (2.1 +/- .02 ml/kg x min; P < 0.005) and diabetic cirrhotics (1.2 +/- 0.2 ml/kg x min; P < 0.0005) compared to that in the control subjects (2.8 +/- 0.2 ml/kg x min). Moreover, there was a highly significant (P < 0.001) negative correlation between basal (MCR)G and the fasting glucose level (r = 0.82), and the degree of glucose intolerance as expressed by the 2-h glucose level determined by the oral glucose tolerance test (r = 0.87). It is concluded that the glucose intolerance of cirrhosis is due to a defect in peripheral glucose utilization.