Tuberous sclerosis complex (TSC) or Bourneville disease is a rare autosomal dominant neurocutaneous disorder that affects various organs. Pulmonary involvement in TSC may consist of lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH), occurring together or alone. In patients with TSC-LAM, chylous pleural effusion (CPE) is a rare, though well-recognized, complication with an unpredictable clinical course. In refractory or persistent CPE, optimal management remains a clinical challenge. We report the unique case of a 29-year-old Caucasian female, neversmoker, with definite TSC since infancy, characterized by seizures, facial angiofibromas ("adenoma sebaceum"), bilateral renal angiomyolipomas, hepatic angiomyolipomas, subcortical/cortical tubers, and subependymal nodules. At 27 years old, due to bleeding from the renal angiomyolipomas, she underwent nephrectomy, first of the right, and then a year and 9 months later, of the left kidney. She was hemodialysis dependent for the next five years until cadaveric kidney transplantation. The medical history was also remarkable for recurrent exudative lymphocytic PE despite repeated therapeutic thoracenteses, with first presentation at 23.5 years of age. Chylothorax was initially diagnosed at 24 years and 8 months old (PE triglycerides 4.53 mmol/L), and reconfirmed at age 29 (PE triglycerides 12.46-15.30 mmol/L). Computerized tomography scan of the thorax showed a large encapsulated PE in the left lung field, multiple thin walled cysts (≤ 5 mm in diameter) in the lung parenchyma bilaterally, and mediastinal lymphadenopathy - all prominent features of LAM - as well as nodular pulmonary lesions (≤ 3 mm in diameter) consistent with MMPH. Given the persistent nature of the CPE, a five-day course of recombinant human factor XIII (FXIII) was administered intravenously. The chylothorax completely resolved within three months. There has been no recurrence of CPE on follow-up chest X-rays (i.e., total follow-up period of 53 months). This report suggests that the transglutaminase FXIII, a blood coagulation factor, may have an important clinical benefit in treating recurrent or thoracentesis-refractory CPE in TSC-LAM. To our knowledge, this is the first known case in the literature describing the successful treatment of CPE with FXIII in TSC-LAM. Because CPE is rare and there is currently no gold standard for its management, regardless of etiology, further research is warranted to investigate the potential clinical use of FXIII as an effective and safe treatment strategy in selected patients.