BackgroundAcquired tracheo-esophageal fistula (TEF) is a rare, life-threatening pathology, responsible for severe comorbidities. Its management is a real therapeutic challenge and remains controversial.Case presentationWe report the first case of endoscopic treatment of TEF by using a porcine small intestine submucosal (SIS) plug device in a young quadriplegic patient after failed surgical closure by cervicotomy. After 1 year of follow-up, oral feeding of the patient was resumed and no clinical signs of fistula recurrence were evident.ConclusionTo our knowledge, we obtained for the first time, a satisfactory result for TEF closure with the use of a porcine SIS plug.