Patients with Nijmegen breakage syndrome (NBS) can develop life-threatening immunodeficiency, which should be treated with hematopoietic stem cell transplantation (HSCT). We report the case of a 14-year-old girl with NBS who due to an increasing number of severe complications was referred for HSCT from a matched unrelated donor. After reduced-intensity conditioning and transplantation of peripheral blood hematopoietic cells, during the early post-transplant period (days 0-30), the girl suffered from severe mucositis, fever episodes, mild acute renal injury and facial vasculitis. All these complications were managed successfully. During the intermediate post-transplant period (days 30-100) a number of hepatic and gastrointestinal complications occurred, including cholecystitis, cholelithiasis with choledocholithiasis, pancreatitis as well as acute bleeding from the lower gastrointestinal tract caused by rectal and recto-sigmoid junction ulcers. All the obstacles were obviously attributable both to the primary congenital disease, its complications, and transplantation itself. We overcame these complications and treated the patient with the best possible and safe methods. The multidisciplinary approach based on combined surgical, endoscopic and conservative management of multiple post-transplant complications was successful for the patient.