T o clarify the role of insulin and growth hormone (HGH) in regulating substrate production for body fuel during prolonged starvation, 6 normal subjects and 10 HGH-deficient dwarfs were fasted for 6 days. Four of these dwarfs received HGH during the fast.Blood glucose concentration decreased a mean 15 mg/100 ml in both controls and HGH-treated dwarfs, but decreased 50 mg/100 ml in untreated dwarfs. The final level at which the blood glucose stabilized was significantly higher in the former two groups (65 ±1.0 mg/100 ml and 88 ±19 mg/100 ml, respectively, versus 39.0 ±4.0 mg/100 ml in the untreated dwarfs). The decline in plasma insulin concentration showed a comparable pattern, decreasing from a similar basal level to 7.7 ±0.4 μU/ml in controls, 8.8 ±1.1 μU/ml in dwarfs treated with HGH, and to a significantly lower level of 3.8 ±1.1 μU/ml in untreated dwarfs. When glucose concentrations were plotted against paired insulin values, the correlation in both dwarfs and normals was significant. In normals, no correlation existed at any time between plasma HGH levels and plasma concentration of either glucose or free fatty acid.Free fatty acid, β-hydroxybutyrate, and acetoacetate increased respectively in normals to peak concentrations in plasma of 1.55 ±0.11, 2.87 ±0.23, and 0.77 ±0.09 mmoles/liter. Untreated dwarfs had significantly greater values of all three (mean maximal concentration: FFA = 2.16 ±0.17 mmoles/liter, β-hydroxybutyrate = 4.11 ±0.34 mmoles/liter, and acetoacetate = 1.16 ±0.10 mmoles/liter). Values returned toward normal in HGH-treated dwarfs. The cahnges in plasma concentrations of β-hydroxybutyrate and acetoacetate were not due to changes in renal excretion.In starvation, the relation between insulin on the one hand and glucose and free fatty acid on the other hand is maintained in the absence of HGH. However, the setting of blood glucose concentration at which this relation takes place is decreased in the absence of HGH. This results in a lower than normal insulin level and, consequently, in a higher than normal free fatty acid concentration.