Objective: The aim of the study was to assess the influence of mechanical ventilation with helium-oxygen mixture (heliox) on basic vital signs, oxygenation, acid-base balance and respiratory mechanics in newborns with respiratory distress syndrome (RDS), previously treated with surfactant. Material and methods: The study was carried out in preterm newborns with respiratory failure requiring mechanical ventilation due to RDS, requiring FiO2≥0.4 after a single dose of surfactant. Patients were ventilated using PCSIMV. Parameters of mechanical ventilation, respiratory function, oxygenation, acid-base balance and vital signs were recorded at baseline, one hour during and one hour after heliox ventilation. Results: Ten newborns with RDS were enrolled in the study. Mechanical ventilation with heliox did not affect vital signs and patient general condition remained stable during and after ventilation with heliox. Mechanical ventilation with heliox was associated with a statistically significant increase in tidal volume (mean 5.48 vs 6.55 ml/kg). There were no significant changes in minute ventilation and peak expiratory flow rate. Mechanical ventilation with heliox allowed the use of significantly lower fractions of inspired oxygen (mean 0.55 vs 0.35), with a significant decrease in the oxygenation index (mean 8.77 vs 5.02) and alveolar-arterial oxygen tension difference (mean 63.81vs113.28 mm Hg). After ventilation with this gas mixture was stopped, the patients required higher FiO2, OI and AaDO2 levels increased. Conclusions: Mechanical ventilation with heliox was safe, improved oxygenation and caused an increase in tidal volume in newborns with RDS previously treated with surfactant.