Morphological changes in the parathyroid glands evidently occur early during renal failure. Histopathological investigations have suggested that parathyroid cells initially increase diffusely with a normal lobular structure (diffuse hyperplasia). The parathyroid glands then become hyperplastic with some nodules (nodular hyperplasia). Cells in nodules grow monoclonally and proliferate aggressively, possibly induced by some kind of genetic abnormality. Pathophysiologically, in cells consisting of hyperplastic nodules, suppression of parathyroid hormone (PTH) secretion under the influence of excess extracellular calcium is more deranged, possibly due to a reduction of calcium-sensing receptors. Vitamin D receptor density decreases more severely in these cells, possibly causing abnormal PTH synthesis, PTH secretion, and even parathyroid cell proliferation. According to histopathological and pathophysiological findings, patients with nodular hyperplasia during renal hyperparathyroidism may be refractory to medical treatments, including calcitriol pulse therapy, and parathyroidectomy will become necessary. There is a relationship between the pattern of parathyroid hyperplasia and glandular weight in which glands weighing more than 500 mg may be pathognomonic of nodular hyperplasia. Glandular volume, estimated by ultrasonography, is one of several important criteria indicating parathyroidectomy. In order to prevent a recurrence of hyperparathyroidism, all nodular hyperplastic tissue should be extirpated.