Exquisite sensitivity of normal parathyroid glands to small changes in ambient calcium concentrations and impaired sensitivity in primary hyperparathyroidism have been shown in vitro. Using an assay for PTH that detects rapid changes in PTH secretion (N-terminal-specific RIA; normal range, less than 3-33 pg/mL), we determined PTH suppressibility in response to a standardized dose of oral calcium in normal subjects and patients with primary hyperparathyroidism. Nine normal subjects were given oral calcium (25 mg/kg), and blood was analyzed half-hourly for 3 h for calcium and N-terminal PTH (N-PTH). Serum calcium rose by 0.34 +/- 0.06 mg/dL (0.085 +/- 0.015 mmol/L), and N-PTH levels declined rapidly from 15.3 +/- 1.4 to 4.2 +/- 1.1 pg/mL (-73 +/- 6%; P less than 0.01). In six subjects N-PTH concentrations became undetectable. Nine patients with primary hyperparathyroidism were tested in the same manner. Serum calcium rose by 0.53 +/- 0.1 mg/dL (0.13 +/- 0.025 mmol/L), and N-PTH levels declined less, from 66 +/- 14 to 52 +/- 12 pg/mL (-21 +/- 4%; P less than 0.05). In none of the patients was the PTH reduced to less than 20 pg/mL. These results illustrate in vivo that the PTH response to oral calcium in primary hyperparathyroidism is markedly different from that in normal subjects.