Abstract Disclosure: D.D. Bagar: None. E. Meyers: None. M. Correia: None. Background: Nivolumab is an immune checkpoint inhibitor that is used to treat specific types of cancer, including melanoma, by increasing the ability of the immune system to detect cancer through activating cytotoxic T-cells. The side effects of immune checkpoint inhibitors are mainly through the overactivation of the immune system that can affect many organs with autoimmune diseases, including endocrine glands, which could be severe and irreversible, like hypothyroidism or immune thyroiditis. The uniqueness of this case is the presence of multifactorial causes of hyperthyroidism; in addition, it is one of the few cases of immune checkpoint inhibitor induced positive TSI thyroiditis.Clinical Case: An 82-year-old male with a known history of atrial fibrillation on amiodarone presented to his dermatologist with a left forearm lesion. A shave biopsy showed melanoma, and he underwent wide local excision with negative sentinel lymph node biopsy. However, he had significant melanoma in situ present within 5 mm of the margin and was deemed not a candidate for further excision. Tumor board recommended close surveillance. He then received two cycles of pembrolizumab for one year, followed by nivolumab. During his treatment course, he had CT scans with iodinated contrast every 8-12 weeks for the clinical trial. At his clinic visit, routine thyroid function tests were significant for hyperthyroidism with a TSH <0.01 and free T4 of 6.07 (0.8-1.8). He was asymptomatic except for unintentional weight loss. He denied using any biotin supplements. His labs also showed positive thyroid stimulating immunoglobulin (TSI) of 1.10 (<=0.54 IU/L). A thyroid US with doppler showed two nodules less than 1.1 cm and no increased vascularity. Amiodarone was discontinued, and prednisone and methimazole were started. His free T4 has since normalized and both prednisone and methimazole are being tapered down. Conclusion: This case is a multifactorial cause of hyperthyroidism. He had been using amiodarone for atrial fibrillation, had multiple imaging studies with iodinated contrast, and was on immune checkpoint inhibitor therapy with a positive TSI. The uniqueness of this case is not only that combined factors can affect thyroid function but also that he developed a positive TSI, which indicates either Graves’ disease or immune-induced thyroiditis by nivolumab, which has been reported only in a few cases. Presentation: 6/3/2024