To evaluate the acute effect of histamine H2-receptor blockade with cimetidine on PTH concentrations and its endogenous biological activity, we studied the effect of iv administration of cimetidine (50-mg bolus followed by 500 mg/60 min infusion) in normal subjects and patients with primary and secondary hyperparathyroidism. No significant changes in serum concentrations of calcium, phosphate, or immunoreactive C-terminal PTH were found in any group. However, the control group had decreased calciuria, increased phosphaturia, and decreased tubular reabsorption of phosphate, while the primary hyperparathyroid group had increased phosphaturia, increased nephrogenous cAMP excretion, and decreased tubular reabsorption of phosphate. In both of these groups, the findings suggest an increase in PTH-like biological activity. These findings suggest that cimetidine is not useful in the diagnosis or medical management of hyperparathyroidism. In fact, the changes in renal calcium and phosphorous excretion indicative of PTH-like biological activity along with a decrease in creatinine clearance in the primary hyperparathyroid group suggest a relative contraindication to the use of this drug in these patients.