The INSURE (Intubation-surfactant-extubation) method has been found to reduce the need for MV, the duration of respiratory support, and the need for surfactant in preterm infants with respiratory distress syndrome (RDS). However, this method fails in some patients. We demonstrated that a birth weight <750 g, pO2/FiO2 <218, and a/ApO2 < 0.44 at the first blood gas analysis were independent risk factor for INSURE failure in infants with gestational age <30 weeks. Moreover, we demonstrated that INSURE treatment can be repeated being the respiratory outcome similar in infants treated with single or multiple INSURE procedures. Thus, it is possible that the multiple INSURE strategy might decrease the failure rate of INSURE and increase its effectiveness in preventing the need for mechanical ventilation (MV).