Excessive or thick pulmonary secretions are a common clinical challenge in the neonatal population. Mucus accumulation can cause many life-threatening complications, including plugging of the endotracheal tube and increasing the risk of pulmonary infections. We report 3 premature neonates who had critical pulmonary collapse secondary to mucous plugging. Different conventional methods to liquefy mucus and facilitate removal of secretions were exhausted to no avail. The rescue use of DNase was effective in reestablishing airway patency. Thus, this drug could be a valuable tool in treating atelectasis and mucus-plugging in mechanically ventilated, premature neonates.