Abstract Disclosure: S. Jain: None. M. Crabtree: None. C. Houston: None. Background: Structural homology between human chorionic gonadotropin (hCG) and thyrotropin stimulating hormone (TSH) allows high levels of hCG to exert thyrotropic effects via TSH receptors. Although hCG-mediated hyperthyroidism is most frequently encountered in the context of pregnancy, it also occurs rarely as a paraneoplastic syndrome. We present a case of hCG-mediated hyperthyroidism due to metastatic choriocarcinoma in a postmenopausal woman. Case Presentation: A previously healthy 59-year-old woman was evaluated for shortness of breath and found to have multiple lung nodules concerning for metastatic malignancy. Further imaging demonstrated an enlarged heterogeneous uterus with an enlarged endometrial cavity. Endometrial biopsy revealed poorly differentiated carcinoma with some areas of possible squamous differentiation. Subspecialty cytopathology review was requested. One week after biopsy, the patient was brought to the emergency department with acute hypoxic respiratory failure following a seizure. She was found to be febrile, tachycardic, hypertensive, and minimally responsive. Head CT revealed a left frontal brain mass with surrounding vasogenic edema, concerning for metastasis. Laboratory evaluation revealed TSH of 0.03 mIU/L (normal 0.35-4.94) and free T4 of 2.30 ng/dL (normal 0.70-1.48). Thyroid stimulating immunoglobulin was negative. Beta-hCG was found to be significantly elevated at 982,093 mIU/mL after 1:100 dilution. She was started on treatment with propranolol, dexamethasone, and chemotherapy with etoposide and cisplatin. Meanwhile, cytopathology review identified scattered cells with features of choriocarcinoma and positive hCG immunostaining, felt to represent a diagnosis of poorly differentiated choriocarcinoma. After one cycle of chemotherapy, the patient’s beta-hCG decreased to 477,668 mIU/mL and free T4 decreased to 1.05 ng/dL. Due to progressive worsening of her clinical status, she was transitioned to palliative care and passed away on hospital day 14. Discussion: Hyperthyroidism mediated by hCG is most often seen in patients with hyperemesis gravidarum, gestational transient thyrotoxicosis, or gestational trophoblastic disease. Our case underscores the importance of considering hCG-mediated hyperthyroidism outside the context of pregnancy. Rare paraneoplastic sources of hCG include choriocarcinoma, seminoma, and other germ cell tumors. Hyperthyroidism in these cases is usually subclinical or mild, but instances of thyroid storm have been reported with metastatic disease. Beta blockers, glucocorticoids, and thionamides can be used as temporizing measures, but definitive therapy requires treatment of the causative malignancy. Presentation Date: Saturday, June 17, 2023