Background Thyroid storm is an endocrinological emergency caused by severe thyrotoxicosis. COVID-19, caused by the novel coronavirus SARS-CoV-2, is known to cause thyroid-related complications of subacute thyroiditis but the occurrence of thyroid storm is rare. The use of first line therapies for thyrotoxicosis/thyroid storm, such as thioamides, radioactive iodine, and surgery, may be precluded by leukopenia, hemodynamic instability, and liver failure, which are commonly seen in severe COVID-19 infection. The necessity for isolation creates a challenge for surgical intervention for these patients. Here we present a unique case of thyroid storm secondary to Graves’ disease, reactivated by COVID-19 infection and managed with therapeutic plasma exchange (TPE). Clinical Case A 56-year-old African American female with history of hyperthyroidism for the past 13 years, presented to the emergency department with sore throat and fatigue for one week prior. On arrival, she was febrile with temperature of 101.1° Fahrenheit, tachycardic with heart rate of 163 bpm and tachypenic with respiratory rate of 41 rpm. Patient had bilateral orbitopathy, tender thyromegaly, thyroid bruit and fine tremors. She also had atrial fibrillation, right-sided heart failure, acute liver failure. Nasopharyngeal COVID-19 testing was positive; laboratory tests revealed TSH <0. 01 uIU/mL (n 0.450 - 5.330), free T4 >5.60 ng/dL (n 0.45 - 1.8), direct bilirubin 1.8 (n 0.1-0.3 mg/dl), mild transaminitis and INR 2.21 (n 0.9-1.1). White blood cell count was 5.4 K/uL (n 4.5-11.5) with 50.8% neutrophils (n 31-76%). Ultrasound of abdomen revealed decompensated cirrhosis with ascites. The Burch-Wartofsky score was 75 points, indicative of thyroid storm. Acute liver failure precluded the use of thioamides; due to the severity of the hyperthyroidism, ablation was not considered. The use of Lugol's iodine was held pending surgical clearance due to active COVID-19 infection. Eventually, patient underwent a total of four sessions of TPE. With each session free T4 levels decreased: 4.12 ng/dl, 2.73 ng/dl, 2.52 ng/dl, and 1.53 ng/dl, respectively. Six days after the last TPE, patient developed complications related to COVID-19 infection and expired before undergoing total thyroidectomy. Conclusion This is a complicated case of a patient with thyroid storm, acute liver failure in the setting of COVID-19 infection. SARS-CoV-2 virus may not only be a trigger for thyroid storm but also represents a challenge in the management of thyroid disease. During TPE, patients’ plasma is extracted from the components of the blood and a colloid replacement solution is infused back. Thyroxine binding globulin bound to thyroid hormones is removed with plasma and colloid replacement provides new binding sites for circulating free thyroid hormone. TPE is effective but rarely used in the past and can be considered as therapeutic for thyrotoxic patients with COVID-19 infection, in whom conventional methods of treatment are not feasible options. Presentation: No date and time listed