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Objective: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequent cause of euvolemic hyponatremia. We present a case of an extremely rare tumor in adults along with SIADH, as well a review of the literature. Methods: A 67-year-old woman was hospitalized following detection of a serum sodium (SNa) level of 112 mmol/L. SIADH of unknown etiology was diagnosed and fluid restriction was initiated, with a partial response. A computed tomography (CT) scan revealed small thoracic nodes as the only finding. The patient was discharged and referred for outpatient follow-up (SNa, 126 mmol/L). After 6 months, chest CT scan and laboratory testing were repeated, with similar results. After a 2-year follow-up, the patient presented with marked weakness again. SNa was 132 mmol/L. Tolvaptan was initiated, with a final dose of 60 mg, with a subsequent 4 mmol/L rise in SNa and excellent tolerance. One year after tolvaptan was started, the patient was hospitalized with severe hyponatremia (115 mmol/L). Results: A chest CT scan showed a mediastinal mass located in the thymus. Vasopressin (AVP) concentration was extremely elevated. The patient underwent tumor resection and was diagnosed with adult neuroblastoma. SNa levels, blood osmolality, and plasma AVP concentration completely normalized 2 weeks after tumor removal. Conclusion: Follow-up and periodic screening for cancer should be considered in long-standing SIADH of unknown etiology. Some patients with extremely high AVP levels may not respond/maintain response to tolvaptan therapy. Determination of AVP levels may be helpful for the management of SIADH in these patients. (AACE Clinical Case Rep. 2016;2:e1-e6) Abbreviations: AVP = vasopressin; CT = computed tomography; P OSM = plasma osmolality; SIADH = syndrome of inappropriate antidiuretic hormone secretion; SNa = serum sodium; U OSM = urine osmolality