The roles of parathyroid hormone (PTH) and calcitonin (CT) in the pathogenesis of familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) are uncertain. Thus we performed studies in 26 patients with FBH, 12 patients with primary hyperparathyroidism (HPT), and 20 normal volunteers, to answer these questions: are plasma levels of intact or biologically active PTH frequently elevated in FBH? Is plasma intact PTH nonsuppressible during calcium infusion? Is there blunting of the C cell CT response to calcium infusion as occurs in primary HPT? We used three methods for measurement of PTH: a mid region-specific radioimmunoassay (iPTH, antiserum GP-1M), an extraction-concentration bioassay (bioPTH, stimulation of cAMP generation in osteoblastlike cells), and a two-site immunoradiometric assay (IRMA) for intact PTH. PTH levels were significantly elevated in primary HPT by all three methods, but mean PTH was normal in FBH and 85-92% of values overlapped the normal range. During 5 minute calcium infusions (2 mg Ca2+ per kg) iPTH values fell little, but bioPTH and intact PTH fell sharply in all three groups. Mean calcium-induced decreases of intact and bioPTH were indistinguishable from normal in FBH, but PTH levels generally remained elevated at 5 minutes in primary HPT. In FBH basal and postinfusion CT levels were normal. The data show that, in the majority of patients with FBH, PTH concentrations and bioactivity in blood are within the normal range and are suppressed rapidly to very low levels with further increases of calcium. The data suggest that the abnormality of parathyroid function in FBH differs from that in primary HPT.(ABSTRACT TRUNCATED AT 250 WORDS)