In order to compare adult, fetal and neonatal metabolism in an acidotic environment, the intracellular NAD reduction rate, tissue oxygen uptake and glucose production were measured fluorometrically, polarographically and enzymatically in isolated perfused adult, fetal and neonatal guinea pig livers at perfusion pHs of 7.40, 6.50 and 6.00, following the administration of norepinephrine (NE), lactate/pyruvate solution (L/P:10/1), octanoate (Oct), ethanol (Eth) and succinate (Succ). The following results were obtained. In the comparison of adult and fetal liver metabolic reactions at a perfusion pH of 7.40, the fetal liver demonstrated approximately half the amount of the metabolic reaction in the intracellular NAD reduction rate, tissue oxygen uptake and glucose productin following the administration of both NE and L/P, indicating the prematurity of fetal metabolism. At a perfusion pH of either 6.50 or 6.00, although the adult liver demonstrated a remarkable decrease in NAD reduction, oxygen uptake and glucose productin following the administration of both NE and L/P, the fetal livers showed a rather enhanced metabolic response acidosis often increasing to 221% increase, at a perfusion pH of 6.50 and 6.00, indicating acidosis tolerance of the fetal cellular metabolism. The perfused neonatal livers demonstrated less glucose production following the administration of NE, and increased glucose production following the administration of NE, and increased glucose production and intracellular NAD oxidation following the administration of L/P. Both fetal and neonatal livers demonstrated prematurity in the metabolic response following the administrations of octanoate and ethanol. However, enhanced metabolic response was observed at perfusion pHs of 6.50 and 6.00.