BACKGROUND Preterm infants can develop many complications related to organs underdevelopment. Respiratory distress syndrome (RDS) is considered the most important cause of morbidity and mortality in these patients. Traditional therapies for severe RDS, such as mechanical ventilation, come with a potential risk for pneumothorax and bronchopulmonary dysplasia while evidence on chest physiotherapy in preterm infants are controversial in terms of feasibility, tolerability and safety. The use of the positive expiratory pressure (PEP) mask is known in the pediatric field especially in cystic fibrosis for the removal of secretions and lung re-expansion. However, no literature exists on the application and effectiveness of this treatment modality for the respiratory rehabilitation of preterm infants. In this study, we aimed to assess the efficacy of a respiratory rehabilitation protocol based on PEP mask in a preterm infant with respiratory distress syndrome. METHODS A Caucasian girl born at 26 + 5 weeks of gestational age with respiratory distress syndrome was treated with mechanical ventilation, oxygen therapy and PEP-mask. CONCLUSIONS Three weeks of PEP mask led to a significant clinical and radiological improvement of the lung's function with progressive reduction of the oxygen supplement and mechanical ventilation until complete weaning off. Given the absence of literature on this subject, further studies should be conducted to confirm these preliminary observations.