The relative contributions of net hepatic glycogenolysis (NHG) and gluconeogenesis to rates of glucose production during a physiological increment in plasma epinephrine concentrations, independent of changes in plasma insulin concentrations, were determined in seven fasting, healthy young subjects. Plasma insulin concentrations were kept constant by infusing somatostatin (0.1 µg/kg/min), and replacing basal insulin (24 pmol/m²/min). Epinephrine (1.2 µg/m2/min) was infused for 90 min while NHG was assessed directly by ¹³C Magnetic Resonance Spectroscopy (MRS). The rate of glucose production was assessed using [6,6-²H₂]glucose, and gluconeogenesis was calculated as the difference between the rate of glucose production and NHG. Plasma epinephrine concentrations increased rapidly from 100 to 2000 pmol/L (P<0.00001) accompanied by an increase in plasma glucose concentrations from 4.3±0.2 to 13.3±0.3 mmol/L at 90 min (P=0.00001). This increase in plasma epinephrine concentration resulted in a 2.5-fold increase in glucose production (from 14.4±1.0 µmol/kg/min to 35.7±2.0 µmol/kg/min, P<0.0001), which lasted for approximately 60min (Phase 1), after which glucose production decreased to 31.2±1.9 µmol/kg/min (P<0.0001 vs. Basal) during the last 30min of the epinephrine infusion (Phase 2). Hepatic glycogen concentrations decreased almost linearly during Phase 1 and rates of NHG were 19.9±3.0 µmol/kg/min (P=0.005 vs. Basal), which could account for ~60% of glucose production. During Phase 2, NHG decreased to 7.3±2.8 µmol/kg/min (P=0.02 vs. Peak), accounting for only ~20% of glucose production. In conclusion, in the presence of basal plasma insulin and glucagon concentrations, a physiologic increase in plasma epinephrine concentrations stimulates glucose production with an initial, 60 min transient phase caused by stimulation of NHG and a second phase, which can mostly be attributed to a two-fold increase in rates of gluconeogenesis.