Primary hyperparathyroidism is a common condition due to either a parathyroid adenoma or, less commonly, parathyroid hyperplasia, whose treatment is essentially surgical. We have, therefore, assessed the accuracy of Tc-99m pertechnetate/Tc-99m sestamibi (methoxy-isobutyl isonitrile) imaging in the localization of adenomas and hyperplastic parathyroids. The clinical records of all patients who had Tc-99m pertechnetate/Tc-99m sestamibi imaging and parathyroid surgery at this hospital were reviewed. The technique used involves standard subtraction methodology with the addition of a novel change detection algorithm to optimize localization. Of 46 patients scanned in 48 patient episodes, 36 patients had adenomas; 28 (78%) were accurately localized to the correct quadrant, and 4 were correctly lateralized. Two patients with parathyroid carcinomas had their metastases correctly localized. Thus, in 34 of 38 (89.5%) of the scans, adenomas or carcinomas were able to be anatomically localized. Six patients presented with hyperplasia; 5 were diagnosed by sestamibi scans, and 3 of these accurately localized all hyperplastic glands. Four additional patients had known hyperplasia, of which 2 were rendered normocalcemic after removal of their sestamibi-positive glands; the other 2 had small second glands detected only at surgery. In patients with unknown pathology, imaging suggested that 6 patients had hyperplasia; this was correct in 5 cases (83%). Nine of the 12 scans in patients who had had previous parathyroid surgery accurately localized the tumors, 7 in the neck and 2 outside. We suggest that sestamibi imaging can help to distinguish hyperplasia from adenomatous disease; when imaging is required, we recommend it as the imaging modality of choice in all patients with primary hyperparathyroidism, especially in reoperated patients.