Most parathyroid adenomas and some pathological parathyroid glands from patients with primary parathyroid hyperplasia or severe uremic secondary/tertiary hyperparathyroidism show an elevated set-point [the extracellular Ca2+ concentration (Ca2+o) half-maximally inhibiting PTH secretion]. In the present study, we investigated whether expression of the Ca2+o-sensing receptor protein recently cloned from bovine parathyroid, a key component in Ca2+o-regulated PTH release, is altered in primary and uremic hyperparathyroidism. Using immunohistochemistry with specific antireceptor antibodies, we compared immunoreactivity of the receptor protein in 14 adenomas, biopsies of 24 normal glands from this same group of patients, and 8 hyperplastic parathyroid glands from 2 individuals with uremic hyperparathyroidism. The results show a substantial reduction in the intensity of immunostaining for the receptor protein that averaged nearly 60% for both adenomas and hyperplastic glands, as quantitated by image analysis. Although normal glands from normocalcemic controls were not available, the intensity of receptor staining in normal glands from patients with adenomas was comparable to that in normal bovine, rat, and mouse parathyroid glands. There was considerable variation in staining intensity among different pathological parathyroid glands, even in those from the same patient with secondary hyperparathyroidism. In addition, both adenomas and hyperplastic glands had, in some cases, isolated chief cells and groups of cells, sometimes around the periphery of an abnormal gland, with receptor staining equivalent to that of normal parathyroid cells, whereas the bulk of the cells in the same gland showed a marked decrease in staining. Thus, there is a variable, but substantial, reduction in the immunoreactivity of the Ca2+o-sensing receptor protein in both parathyroid adenomas and uremic hyperparathyroidism, as assessed by immunohistochemistry, that probably results from reduced expression of the receptor protein and may contribute to the increase in the set-point often observed in these patients.