Increased urinary excretion of cAMP is a common finding in patients with primary hyperparathyroidism. We report a patient with hypercalcemia, primary hyperparathyroidism, vitamin D deficiency and high nephrogenous cAMP that fell to low levels during the course of a protracted illness. Surgical removal of a large parathyroid cystic adenoma was associated with a decrease in plasma calcium. Because of the relatively low nephrogenous cAMP with high plasma iPTH the biological activity of the fluid aspirated from the adenoma was examined. Acute clearance studies were performed in parathyroidectomized rats and their response to the parathyroid fluid was compared with the response of synthetic PTH. Similar phosphaturic responses to PTH and the aspirated fluid were recorded and were preceded by similar increments in nephrogenous cAMP. Thus the discrepancy between the high plasma calcium, high PTH and the low nephrogenous cAMP seen in our patient was related to impaired cAMP production by the renal adenylate cyclase. There was no evidence for a hormone with a different biological activity. The impaired formation of cAMP may reflect a combined result of several factors including downregulation of renal adenylate cyclase, phosphate depletion and vitamin D deficiency state.