Although potentially useful in the understanding of hypercalcemic states, a satisfactory animal model of primary hyperparathyroidism has not been developed. Models that use transplants of supernumerary parathyroid (PT) glands or chronic parathyroid hormone (PTH) infusion are not ideal for many reasons. We report a new animal model in which athymic nude mice were used as recipients of human PT tissue heterografts. Three groups received 14, six, or one piece of PT adenoma tissue, and one group received six pieces of normal PT tissue. The significantly higher PTH levels in mice that received adenoma heterografts versus those with similar amounts of normal tissue suggest that adenomatous tissue is functionally distinct. A dose-response relationship between induction of hypercalcemia and the number of pieces implanted was in evidence, although only a small percentage of the mice with high PTH levels developed hypercalcemia. This differential response could be the result of any of several factors: (1) loss of ability to secrete bioactive PTH, (2) differing secretion rates among donor adenomas, (3) variability in host responsiveness to human PTH, and (4) requirement of additional factor (s) to generate consistently the hypercalcemia characteristic of human primary hyperparathyroidism.