The two most frequent causes for hypercalcemia are primary hyperparathyroidism and hypercalcemia associated with malignancy. Elevated or inappropriately high PTH serum levels are the hallmark of hyperparathyroidism. Sensitive immunometric assays for the secreted, biologically active, intact parathyroid hormone molecule, PTH-(1-84), employ two populations of region-specific antibodies, take advantage of saturation kinetics rather than competitive binding, and have many technical advantages over conventional radioimmunoassay. Approximately 90% of patients with primary hyperparathyroidism have elevated serum levels of PTH-(1-84) by immunometric assay; the remainder have inappropriately elevated values of PTH for the serum calcium concentration. Clinical correlation studies comparing measurements of PTH using antisera that recognize the carboxyl, midregion, or amino terminus of PTH with PTH levels determined by immunometric assays demonstrate elevated values in equivalent numbers of hyperparathyroid individuals. Immunometric assays for PTH-(1-84) have their greatest value in separating patients with hyperparathyroidism from those with hypercalcemia of malignancy. In earlier studies using region-specific antisera, there was virtually always an overlap of serum PTH levels in hyperparathyroidism and hypercalcemia associated with malignancy. In contrast, analysis of results using PTH-(1-84) immunometric assays in several hundred reported patients shows a complete separation of PTH values. Clinical judgment, combined with measurement of PTH in the setting of hypercalcemia, can lead to the diagnosis of hyperparathyroidism with confidence in essentially all patients.