Introduction Esophago-pleural fistula (EPF) is a rare surgical complication with important morbidity and mortality. Generally, EPFs present as a recurrent or chronic respiratory infection, empyema, or hemorrhage. Diverse diagnostic and multimodal treatment strategies can be considered including stenting, endoluminal clipping, as well as surgical repair. We present the diagnostic and therapeutic challenges of a unique case of EPF after bilateral lung transplantation (BLTx). Case Report A 62-year-old male with scleroderma and secondary pulmonary arterial hypertension underwent BLTx under VA-ECMO for acute deterioration of his underlying lung fibrosis. Early recovery was uncomplicated with weaning from ECMO on post-operative day (POD) 2, successful extubation on POD 3 and discharge to the ward on POD 13. However, 2 days later he developed acute respiratory distress due to a right-sided pneumothorax. Chest drainage did not suffice and on POD 18 a thoracoscopic exploration for empyema was performed. On POD 26, semi-digested food was seen in the chest tube. Esophagogastroscopy with methylene blue confirmed leakage and two separate EPFs. Nil per os policy was started. On POD 32 endoluminal clipping was attempted and esophagogastroscopy showed healing of the upper fistula, though persistence of the lower one. Additional clipping of the distal EPF was performed. Despite clinical improvement, a new esophagogastroscopy on POD 71 revealed a new fistula between the endoluminal clips. Ultimately, the EPF was primarily closed and covered with an intercostal muscle flap trough right-sided thoracotomy on POD 105. Nine days after surgical closure, a contrast esophagogram showed no residual leakage. The patient experienced a slow but gradual recovery and oral intake was started successfully. At 2.5 years post-BLTx, the patient has a normal oral intake and spirometry shows a good pulmonary function without signs of rejection or chronic lung allograft dysfunction. Summary Post-operative EPF is a life-threatening situation, especially in immunocompromised patients. A low threshold of clinical suspicion and esophagogastroscopy are warranted to impede the diagnosis of EPF. In our experience, minimal invasive endoscopic strategies should be considered first, however, surgical treatment with primary suture and muscle coverage has the highest chance to be effective. Esophago-pleural fistula (EPF) is a rare surgical complication with important morbidity and mortality. Generally, EPFs present as a recurrent or chronic respiratory infection, empyema, or hemorrhage. Diverse diagnostic and multimodal treatment strategies can be considered including stenting, endoluminal clipping, as well as surgical repair. We present the diagnostic and therapeutic challenges of a unique case of EPF after bilateral lung transplantation (BLTx). A 62-year-old male with scleroderma and secondary pulmonary arterial hypertension underwent BLTx under VA-ECMO for acute deterioration of his underlying lung fibrosis. Early recovery was uncomplicated with weaning from ECMO on post-operative day (POD) 2, successful extubation on POD 3 and discharge to the ward on POD 13. However, 2 days later he developed acute respiratory distress due to a right-sided pneumothorax. Chest drainage did not suffice and on POD 18 a thoracoscopic exploration for empyema was performed. On POD 26, semi-digested food was seen in the chest tube. Esophagogastroscopy with methylene blue confirmed leakage and two separate EPFs. Nil per os policy was started. On POD 32 endoluminal clipping was attempted and esophagogastroscopy showed healing of the upper fistula, though persistence of the lower one. Additional clipping of the distal EPF was performed. Despite clinical improvement, a new esophagogastroscopy on POD 71 revealed a new fistula between the endoluminal clips. Ultimately, the EPF was primarily closed and covered with an intercostal muscle flap trough right-sided thoracotomy on POD 105. Nine days after surgical closure, a contrast esophagogram showed no residual leakage. The patient experienced a slow but gradual recovery and oral intake was started successfully. At 2.5 years post-BLTx, the patient has a normal oral intake and spirometry shows a good pulmonary function without signs of rejection or chronic lung allograft dysfunction. Post-operative EPF is a life-threatening situation, especially in immunocompromised patients. A low threshold of clinical suspicion and esophagogastroscopy are warranted to impede the diagnosis of EPF. In our experience, minimal invasive endoscopic strategies should be considered first, however, surgical treatment with primary suture and muscle coverage has the highest chance to be effective.