Measurement of bioactive parathyroid hormone (PTH) is essential for optimal management of bone abnormalities in dialysis patients. This can be accomplished by PTH measurements using third-generation PTH assays, which detect more or less of the first six amino acids of the PTH structure. Such assays do not detect non-(1-84) PTH fragments, such as human PTH (7-84), which are recognized by the second-generation PTH assays that use a detection antibody that recognizes an epitope within the 13-34 region of the PTH structure. Therefore, third-generation PTH results are expected to be lower than those that are obtained with second-generation PTH assays. Rare exceptions to this rule have been reported for patients with severe primary hyperparathyroidism or parathyroid cancer. Sera and gland extracts were analyzed from a dialysis patient with high bone turnover disease and with surprising higher PTH levels by a third-generation assay than by a second-generation assay. This finding normalized after the surgical removal of an enlarged gland with a single nodule, an advanced type of nodular hyperplasia. HPLC fractionation of sera and gland extracts revealed the overproduction and secretion of a PTH molecule with an intact amino-terminus structure distinct from (1-84) PTH. This form of PTH was readily detectable by third-generation PTH assays but was poorly reactive in second-generation PTH assays. Therefore, parathyroid glands with advanced uremic nodular hyperplasia may overproduce and secrete a novel, biologically active form of PTH with an intact 1-6 region but a presumably modified 12-18 region required for the detection in second-generation PTH assays.