Summary Background Management of children with gastroesophageal reflux disease (GORD) and difficult-to-treat (D-T-T) respiratory symptoms may include double fiberoptic, airway and oesophago-gastro-duodenoscopies (DE). A study was performed to evaluate the usefulness and safety of DE in children with severe GORD and D-T-T respiratory symptoms. Methods A 3-year retrospective review of records of children who underwent DE under general anaesthesia was performed: the relevant clinical information obtained and the occurrence of complications in the 72 h following the DE. Results Inflammatory changes of the airways were found at bronchoscopy in 40 out of the 60 children: bronchoalveolar lavage (BAL) demonstrated positive lipid-laden alveolar macrophages (LLAM), neutrophilic inflammation or both, respectively in 9, 12 and 16 patients. BAL bacterial cultures were positive in 2 patients with elevated airway neutrophilia. Structural airway abnormalities, explaining not GOR-related D-T-T respiratory symptoms were identified in 11 patients. Oesophagoscopic findings supporting GORD were detected in 32/60 children and confirmed by consistent histological changes in oesophageal mucosal biopsies (OEB) in 27. The frequency of complications, all minor, was low during the procedure and in the following 72 h. They included mild desaturation, stridor or bronchospasm, vomiting, dysphagia and hyperthermia requiring antibiotic treatment in 1 patient. No “new onset” complication was observed after 48 h following DE. The time-dependent hazard of complications was significantly higher for patients with a history of onset of respiratory symptoms early in life (≤2 years of age) ( p = 0.038). Conclusion DE can be useful in the clinical evaluation of children with D-T-T respiratory symptoms and GORD and is associated with low frequency of mild complications when performed by appropriately trained and experienced personnel.