We investigated cAMP metabolism during and after a 15-min infusion of parathyroid hormone (PTH) in 7 normals, 13 patients with typical primary hyperparathyroidism (1HPT), and 6 patients with familial hypocalciuric hypercalcemia (FHH). Nephrogenous urinary cAMP excretion rate reached a peak during the first or second 30 min urine collection interval after the start of the PTH infusion in all subjects. cAMP concentration in plasma reached a peak within 5--20 min of the start of the infusion and then decreased with an initial half-time of 15 min. The peak value of nephrogenous urinary cAMP excretion rate was lower in the group with 1HPT than in the group with FHH or in normals (119 vs, 275 vs. 204 nmol/100 ml glomerular filtrate; P less than 0.0 5 for both comparisons). Similarly, the peak value of plasma cAMP concentration was less in 1HPT subjects than in FHH patients or in normals (11.1 vs. 17.1 vs. 16.6 nmol/100 ml, respectively; P less than 0.05 for both comparisons). For purposes of diagnostic classification, the two hypercalcemia groups could be more completely separated by the values of either the renal calcium to creatinine clearance ratio or the plasma PTH concentration than by the values of inidices of cAMP response to PTH. The differences in cAMP response to PTH between FHH and 1HPT patients could be secondary to differences in circulating PTH concentrations (these are lower in subjects with FHH) or could reflect a renal lesion more closely related to the underlying etiology of FHH.