The use of exogenous surfactant in the clinical management of severe neonatal respiratory distress syndrome (RDS) has raised some potential new problems related to the rapid variations in oxygenation and pulmonary compliance occurring after this treatment. We advise a strict monitoring of arterial oxygen tension (Pao2), preferably by a non-invasive technique and rapid resetting of the ventilator as indicated by changes in pulmonary compliance and lung aeration after surfactant administration. The goal should be to minimize the risks of air leakage, left-to-right shunt, and overloading of the pulmonary circulation. Rapid diagnosis and treatment of patent ductus arteriosus and appropriate fluid intake are also essential for a favourable outcome in newborn infants with severe RDS treated with surfactant.