We examined by microsatellite allelotyping 69 hyperplastic lesions of the parathyroid glands from 23 patients with refractory, uremic hyperparathyroidism. Allelic changes, at least at one chromosomal arm, were found in 31 of the 69 lesions (43%). Alteration at a single chromosome was seen in 14 lesions and at two to four chromosomes in 11 lesions, and there were five to eight alterations in 5 nodules. Allelic imbalance occurred most frequently at chromosome 7p between the EGFR gene and locus D7S817 (16%), at 18q between loci D18S61 and D18S70 (14%), and at chromosome 2 between D2S380 and D2S1391 (9%). X-inactivation study showed a monoclonal growth in 18 of 29 nodules in females, and a loss of the Y chromosome was seen in 8 of the 39 nodules obtained from males. Our results suggest that the uremic "hyperplastic" nodules have a molecular pathway distinct from those known for sporadic primary parathyroid adenomas.