We investigated the possible involvement of parathyroid hormone-related protein (PTHrP) in 2 cases of metastatic pancreatic neuro-endocrine tumors associated with severe hypercalcemia. Both patients displayed biochemical alterations in renal tubular reabsorption of calcium and phosphate, as well as in urinary cAMP excretion, similar to those encountered in primary hyperparathyroidism, although plasma levels of parathyroid hormone were within the normal range. Tumor protein extracts stimulated cAMP production, which was inhibited by the PTH-antagonist (8,18 Nle, 34 Tyr)bPTH-(3-34)amide, in the PTH-responsive osteoblastic cell line UMR-106. Northern blot analysis of tumor extracts revealed the presence of PTHrP mRNA transcripts, while PTH mRNA was undetectable. In contrast, neither PTHrP mRNA(s) nor cAMP-stimulating activity was detectable in other neuroendocrine tumors not accompanied by hypercalcemia. These results demonstrate that certain pancreatic neuroendocrine tumors associated with hypercalcemia can synthesize and release PTHrP.