We describe the case of an unusually large (giant) cystic intrathyroid parathyroid adenoma in a 73-year-old woman who had a 1-year history of hypercalcemia and a 5-year history of an asymptomatic enlargement of the left lobe of the thyroid. This unique case highlights the potential difficulties that can arise in the evaluation of thyroid nodules in patients with hyperparathyroidism. These difficulties were accentuated in this case by the large size of the mass, its intrathyroid location, and cytologic features that were compatible with a lesion of thyroid origin. In some cases, including this one, even a thorough preoperative evaluation that includes fine-needle aspiration biopsy and radiographic and nuclear medicine studies may not allow for a definitive preoperative diagnosis. The histologic overlap between thyroid and parathyroid lesions can also be problematic at the time of intraoperative frozen-section evaluation. Intraoperative parathyroid hormone monitoring may be helpful in these difficult cases.