Summary: Response to a primed glucose infusion (0.5 g/kg injected over 3 min and 8 mg/kg/min infused for 3 hr) was studied in 5 term and 11 preterm rhesus monkey neonates 2–3 hr after delivery by cesarian section. The glucose challenge perturbed a steady state glucose specific activity achieved in the previous 100 min by a primed trace infusion of 2-[3H]glucose (6 μCi and 0.2 μCi/min). This allowed the determination of changes in endogenous glucose turnover in response to exogenous glucose in the immediate newborn period. With glucose challenge, the 5 term animals and 6 of the 11 preterm animals developed a new steady state glucose concentration (80–100 ml/dl). Coincident with this was a marked reduction in endogenous hepatic glucose output and a moderate increase in peripheral glucose utilization as measured by the tracer methodology. In contrast, the other five preterm monkeys developed hyperglycemia upon glucose challenge (190–210 mg/ dl). All groups had similar glucose-stimulated insulin release which peaked after 60 min of glucose infusion. However, in comparison to the other groups, the group that was to develop hyperglycemia exhibited: (1) lower basal insulin and higher basal glucose values; (2) no suppression of endogenous hepatic glucose output or lipolysis despite glucose-stimulated insulin release; (3) lower birth weight and gestational age, and increased eventual mortality. Hypoxia was not evident in any group as evidenced by clinical signs and decreasing lactate/ pyruvate ratios during the glucose infusions. Speculation: The inability of certain preterm rhesus monkeys to maintain normoglycaemia, but rather to develop hyperglycemia in the face of a glucose infusion might be related to inappropriate adrenergic activity unrelated to cither hypoxia or hypothermic stress. This represents an animal model for the further study of hyperglycemia seen in certain human preterm neonates.