Background: Primary synovial sarcoma (SS) of the thyroid (PSST) is extremely rare. Its differential diagnosis from other neoplasms is essential since it has different management protocols and prognosis. Case: A 26-year-old man with a 4.5-cm solid lobulated mass was seen at an outside hospital. Fine needle aspiration (FNA) was interpreted as a papillary carcinoma, and a total thyroidectomy was performed. The final histologic diagnosis was spindle epithelial tumor with thymus-like differentiation (SETTLE). No metastases were detected at that time, and the patient received radioactive iodine treatment. Two years post-surgery, he was seen at our hospital with a local recurrence, and FNA was considered as consistent with SETTLE. The mass was resected, and a left modified radical neck dissection was performed. The tumor revealed necrosis and a high mitotic index. Following histologic, immunohistochemical, and molecular studies, the tumor was classified as a PSST. The patient received chemotherapy and targeted immunotherapy, but he died 41 months after the initial presentation. Conclusion: The main diagnostic pitfall of PSST is SETTLE. The presence of mitotic figures and basal lamina material, negative staining for smooth muscle actin, and positive staining for transducer-like enhancer of split 1 antibody favor SS over SETTLE. SYT gene rearrangement is essential to establish the definitive diagnosis of PSST.

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