In the neonatal period, the human kidney is characterized by an impaired ability to regulate water and sodium homeostasis, resembling partial aldosterone resistance. The aim of our study was to assess this hormonal insensitivity in newborn infants and to determine its relationship with neonatal sodium handling. We conducted a prospective study in 48 healthy newborns and their mothers. Aldosterone, renin, and electrolyte concentrations were measured in umbilical cords and in maternal plasma. Urinary aldosterone concentrations and sodium excretion were determined at urination within 24 h after birth. A significant difference was observed between aldosterone and renin levels in newborn infants compared with their mothers (817 +/- 73 versus 575 +/- 55 pg/mL and 79 +/- 10 versus 15 +/- 2 pg/mL, respectively, p < 0.001). This hyperactivation of the renin-angiotensin-aldosterone system was associated with hyponatremia and hyperkalemia in the newborn infants, and high urinary sodium loss, consistent with a partial aldosterone resistance at birth. Unlike plasma aldosterone, urinary aldosterone concentration was found highly correlated with plasma potassium concentrations, thus representing the best index for accurate evaluation of mineralocorticoid sensitivity. Our study represents a comprehensive characterization of the renin-aldosterone axis in newborn infants and provides evidence for physiologic partial aldosterone resistance in the neonatal period.