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Background Surgery in patients affected by amyotrophic lateral sclerosis (ALS) presents a particular anesthetic challenge because of the risk of post-operative pulmonary complications. Aims of the study We report on the use of non-invasive ventilation (NIV) to prevent post-operative pulmonary complications (PPCs) in nine patients affected by ALS enrolled in a phase-1 clinical trial with stem cell transplantation. Methods All patients were treated with autologous mesenchymal stem cells implanted into the spinal cord with a surgical procedure. Anesthesia was induced with propofol and maintained with remifentanil and sevoflurane. No muscle relaxant was used. After awakening and regain of spontaneous breathing, patients were tracheally extubated. Non-invasive ventilation through nasal mask was delivered and non-invasive positive pressure ventilation and continuous positive pressure ventilation were started. Results The average time on NIV after surgery was 3 h and 12 min. All patients regained stable spontaneous breathing after NIV discontinuation and had no episodes of respiratory failure until the following day. Conclusions Our case series suggest that the use of NIV after surgery can be a safe strategy to prevent PPCs in patients affected by ALS. The perioperative procedure we chose for these patients appeared safe even in patients with advanced functional stage of the disease.