BACKGROUND: Male preterm infants are more likely to experience RDS than females. Our objectives were to determine if sex-related differences in physiological adaptation after preterm birth increase with time after birth and if the use of continuous positive airway pressure (CPAP) reduces these differences. METHODS: Unanaesthetized lambs (9F, 8M) were delivered at 0.90 of term. Blood gases, metabolites, cardiovascular and respiratory parameters were monitored in spontaneously breathing lambs for 8h. Supplemental oxygen was administered via a face mask at 4 cmH2O CPAP. At 8h, lung compliance was determined and bronchoalveolar lavage fluid (BALF) analysed for total protein and surfactant phospholipids. Surfactant protein (SP) gene expression and protein expression of SP-A and pro-SP-C were determined in lung tissue. RESULTS: For 8h after delivery, males had significantly lower arterial pH, higher PaCO2 and a greater percentage of males were dependent on supplemental oxygen than females. Inspiratory effort was greater and lung compliance lower in male lambs. Total protein concentration in BALF, SP gene expression and SP-A protein levels were not different between sexes; pro-SP-C was 24 lower in males. CONCLUSION: The use of CPAP did not eliminate the male disadvantage, which continues for up to 8 hours after preterm birth.Pediatric Research (2015); doi:10.1038/pr.2015.175.