The effect of increased glycogenolysis, simulated by galactose's conversion to glucose, on the contribution of gluconeogenesis (GNG) to hepatic glucose production (GP) was determined. The conversion of galactose to glucose is by the same pathway as glycogen's conversion to glucose, i.e. glucose-1-P glucose-6-P glucose. Healthy men (n = 7) were fasted for 44 h. At 40 h hepatic glycogen stores were depleted. GNG then contributed ~90% to a GP of ~8 µmol/kg/min. Galactose, 9 g/h, was infused over the next 4 h.. The contribution of GNG to GP declined from ~90% to 65%, i.e. by ~2 µmol/kg/min. The rate of galactose conversion to blood glucose, measured by labeling the infused galactose with [1-²H]galactose (n = 4), was also ~2 µmol/kg/min. The 41^st h GP rose by ~1.5 µmoles/kg/min and then returned to ~9 µmol/kg/min, while plasma glucose concentration increased from ~4.5 to 5.3 mM, accompanied by a rise in plasma insulin concentration. Over 50% of the galactose infused was accounted for in blood glucose and hepatic glycogen formation. Thus, an increase in the rate of GP via the glycogenolytic pathway resulted in a concomitant decrease in the rate of GP via GNG. While the compensatory response to the galactose administration was not complete, since GP increased, hepatic autoregulation is operative in healthy humans during prolonged fasting.