We studied the rate of endogenous glucose production and disappearance in a group of 10 clinically stable < 1100 gm infants in the first week of life, using stable-isotope (6,6-2H-glucose) dilution analysis for a 2-hour study period. Plasma glucose and insulin concentrations at 2 hours were 5.4 +/- 2.5 mmol/L (97 +/- 15 mg/dl) and 71.4 +/- 2.9 pmol/L, respectively, and did not change during the study period. The rate of glucose disappearance was 37 +/- 10 mumol/kg (6.77 +/- 0.55 mg/kg) per minute. The rate of endogenous glucose production was 12.3 +/- 11 mumol/kg (2.22 +/- 0.61 mg/kg) per minute. The exogenous glucose infusion rate was 25.2 +/- 8.4 mumol/kg (4.54 +/- 0.47 mg/kg) per minute. Endogenous glucose production was correlated with plasma glucose concentration (r = 0.76; p < 0.05) and the rate of glucose disappearance (r = 0.75; p < 0.05); plasma glucose concentration was correlated with the rate of disappearance (r = 0.87; p = < 0.01) and insulin concentrations (p < 0.05). We conclude that infants who weight < 1100 gm utilize three to four times more glucose per kilogram of body weight than adults, reflecting their higher ratio of brain to body weight. Endogenous glucose production provided only approximately one third of the glucose needed--a mandate for the exogenous infusion of glucose to prevent the development of hypoglycemia.