Successful adaptation to air-breathing at birth depends on rapid clearance of fetal lung liquid from the lung lumen. Liquid absorption is mediated by activation of amiloride-sensitive Na+ channels in the respiratory epithelium. To test the relationship between respiratory epithelial Na+ transport and development of RDS, we measured nasal transepithelial potential difference (PD) in 32 very preterm (≤30 weeks gestation) newborn infants. Maximal PD increased with birth weight (1.2m V/100g). Infants were retrospectively assigned to RDS (22 infants) and non-RDS (10 infants) groups, based on clinical and chest X-ray criteria. Maximal PD was lower in RDS infants (-16.5±0.6 mV) than in non-RDS infants (-22.0±1.1 mV). Na+ absorption across nasal epithelium, determined by amiloride-sensitive inhibition of PD within the first 24 hours of life, was significantly lower in infants who developed RDS (29.5±1.1% inhibition) than in non-RDS infants (40.8±1.7% inhibition). Infants without RDS had PD values similar to normal full-term infants. Maximal and amiloride-sensitive PD normalized during the recovery phase of RDS. We conclude that 1) Na+ absorption across nasal epithelium increases with increasing birth weight, and 2) impairment of Na+ absorption across the respiratory epithelia of very preterm infants may contribute to the etiology of RDS.