The hepatic uptake of unlabeled insulin (5--50 mU/kg) was determined in 45 nondiabetic patients without hepatic disease. Thirty patients were studied at normoglycemia and 15 at moderate steady hyperglycemia, induced by intraportal infusion of 80 or 200 mg glucose per h and per kg. The first pass fractional hepatic uptake of insulin (FH) was estimated by comparing the results after a portal and a peripheral infusion of unlabeled insulin in each patient. It varied negatively with the amount of insulin given, decreasing about 50% after a tenfold increase in dose. FH was markedly smaller during steady hyperglycemia than at normoglycemia, regardless of insulin dose. For low doses (5--10 mU/kg), giving insulin concentrations within the physiological range, FH was 0.43 (5 mU/kg) and 0.40 (10 mU/kg) at normoglycemia and 0.16 (10 mU/kg) at hyperglycemia. FH did not vary with the fasting or the glucose-stimulated, endogenous insulin levels recorded before insulin infusion. It is suggested that glucose is more important than insulin in modulating the fractional hepatic uptake of insulin.