Background: Ventilator induced lung injury prevention may begin from birth, and respiratory support without endotracheal intubation is an attractive option in preterm baby with Respiratory distress syndrome (RDS). The objective of the study was to evaluate the clinical course and respiratory outcomes in preterm infants with moderate RDS assigned from birth to Nasal Continuous Positive Airway Pressure (NCPAP) or Bi-level Nasal Continuous Positive Airway Pressure (Bi-level NCPAP).Methods: 60 infants of 28-34 weeks GA (<35 wks GA), affected by moderate RDS, were considered eligible and were randomized to NCPAP (CPAP level=6cm H2O, Group A n=30) or to Bi-level NCPAP (lower CPAP level=4.5 cmH2O; higher CPAP level=8 cmH2O, Group B n=30), provided with the variable flow devices (Infant Flow CPAP vs Infant Flow SiPAP™, Viasys Healthcare, Yorba Linda, CA).Results: Length of ventilation, oxygen dependency, need for intubation and occurrence of air leaks were considered as outcomes. Infants showed similar characteristics at birth (Group A versus Group B: GA 30.4±2 wks versus 30.3±2wks, BW 1433±545g versus 1415±560g. Group A underwent longer respiratory support (6,2±2 days versus 3,8±1 days, p=0.025), longer O2 dependency (13,8±8 days versus 6,5±4 days, p=0.027) and was discharged later (GA at discharge 36,7±2,5 weeks versus 35,6±1,2 weeks, p=0.02). All infants survived. No BPD or neurological disorders occurred.Conclusions: Bi-level NCPAP was associated with better respiratory outcomes versus NCPAP, and allowed earlier discharge, inducing the same changes in the cytokine levels. In our population, it was well tolerated and safe