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Tumors of the parathyroid glands are the second most common endocrine neoplasia. Epigenetic studies revealed an embryonic signature involved in parathyroid tumorigenesis. Here, we investigated the expression of the stem core genes <i>SOX2, POU5F1/OCT4,</i> and <i>NANOG</i>. Rare cells within normal parathyroid glands expressed <i>POU5F1/OCT4</i> and <i>NANOG</i>, while <i>SOX2</i> was undetectable. Nuclear <i>SOX2</i> expression was detectable in 18% of parathyroid adenomas (PAds, <i>n</i> = 34) involving 5–30% of cells, while <i>OCT4</i> and <i>NANOG</i> were expressed at the nuclear level in a more consistent subset of PAds involving 15–40% of cells. Most parathyroid carcinomas expressed the core stem genes. <i>SOX2</i>-expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures, silencing of the tumor suppressor gene <i>MEN1</i> induced the expression of <i>SOX2</i>, likely through a <i>MEN1/HAR1B/SOX2</i> axis, while calcium-sensing receptor activation increased <i>SOX2</i> mRNA levels through <i>YAP1</i> activation. In addition, inducing nuclear β-catenin accumulation in PAds-derived primary cultures by short-term incubation with lithium chloride (LiCl), <i>SOX2</i> and <i>POU5F1/OCT4</i> expression levels increased, while <i>NANOG</i> transcripts were reduced, and LiCl long-term incubation induced an opposite pattern of gene expression. In conclusion, detection of the core stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.