To determine the postnatal changes in mineralocorticoid action on the cortical distal nephron in preterm neonates, we evaluated the transtubular potassium gradient (TTKG) and its relationship to other renal and non-renal parameters in 16 preterm neonates during the first 5 weeks of life. Preterm neonates were divided into two groups according to their gestational age: the first group (group A, n=9) had a gestational age less than 30 weeks and the second group (group B, n=7) had a gestational age over 30 weeks. TTKG in both groups increased significantly with postnatal age, and TTKG in group A was significantly lower than that in group B (P=0.0003; two-way repeated analysis of variance). TTKG in group A was significantly lower during the 2 weeks of postnatal life than that in full-term neonates [TTKG during 1st week (mean+/-SD) 3.73+/-1.32, P<0.00001; during 2nd week 7.77+/-3.60, P=0.0096 versus full-term neonates (n=19); 11.56+/-3.23]. TTKG in group B was significantly lower only during the 1st week of life (6.55+/-2.71, P=0.0013) compared with full-term neonates. Plasma aldosterone concentration did not correlate with TTKG value. Stepwise regression analysis showed that postnatal age, cortical lumen sodium concentration (CLNa), and clinical condition requiring the use of mechanical ventilation were independent variables that correlated significantly with TTKG. We postulate that the low TTKG level in preterm neonates might reflect the prematurity of renal function (early postnatal age, CLNa) and the condition(s), relating to immaturity, such as the use of mechanical ventilation.