BACKGROUND: Tumor lysis syndrome (TLS) is an extremely rare complication of solid tumors and is more frequently observed in patients-with hematologic malignancies. This report describes a novel approach to the management of a rare case of TLS in metastatic gestational trophoblastic neoplasia (GTN). CASE: A 17-year-old female presented 8 weeks postpartum with severe anemia, thyrotoxicosis, and elevated serum beta-human chorionic gonadotropin (beta-hCG). Imaging studies confirmed metastatic GTN to the lungs. The patient developed grade 4 TLS after the first cycle of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA-CO). She did not respond to standard treatment of aggressive hydration and allupurinol and continued to be in renal failure with elevated uric acid. A single dose of recombinant urate oxidase, rasburicase, rendered the uric acid level undetectable in 3 days and completely reversed the renal failure, avoiding hemodialysis. Three more cycles of EMA-CO were then administered. Subsequently, the patient developed congestive heart failure and was switched to single-agent actinomycin-D. beta-hCG became negative after 5 cycles, and her ejection fraction returned to baseline. CONCLUSION: This is a rare case of TLS in the setting of metastatic GTN. To our knowledge this is the first reported case of utilizing rasburicase for the management of TLS in GTN. (J Reprod Med 2010;55:441-444)