Objectives: To examine the success rate of less invasive surfactant administration (LISA), to identify early predictive factors for the outcome of LISA and to compare neonatal outcomes between the LISA failure group and the group of infants who were succesfully treated with LISA. Design: A retrospective cohort study. Patients: Infants born at less than 33 weeks of gestation (n=158) and treated with LISA for respiratory distress syndrome. Results: LISA was successful in 86 cases (54.4%), 72 preterm infants (45.6%) needed additional surfactant therapy and/or mechanical ventilation in the first 72 hours. In a multivariate logistic regression analysis, six independent predictors were identified: core temperature at the time of admission (adjusted OR 3.56), suboptimal dose of surfactant (adjusted OR 0.254), elevated CRP (>10 mg/L) at 24 hours of life (adjusted OR 0.28), highest respiratory severity score during the first hour of life or at the time of LISA (adjusted OR 0.463), maternal age (adjusted OR 0.923) and birth weight (adjusted OR 1.003). The ROC curve created by using the identified factors indicates good predictive power with an area under the curve of 0.85. LISA failure was associated with a substantially higher risk of pneumothorax, bronchopulmonary dysplasia, intraventricular hemorrhage, severe retinopathy of prematurity, longer duration of mechanical ventilation and prolonged length of hospital stay. Conclusion: Failure of LISA is relatively frequent event in very preterm infants and is associated with adverse outcomes. Prevention of hypothermia during early stabilization and appropriate dosing of surfactant increase may LISA success rates and improve patient outcome.