Objective: To compare the clinical and biochemical features, bone densitometry data, and results of diagnostic imaging to localize parathyroid tumors in patients with radiation-associated hyperparathyroidism (R-HPT) and patients with HPT who had no history of radiation exposure (NR-HPT). Methods:We performed a retrospective analysis of 34 patients with HPT who underwent evaluation and subsequent neck exploration between 1990 and 1995. We recorded and compared the symptoms, biochemical findings, bone densitometry data, results of diagnostic imaging, and pathologic findings in R-HPT and NR-HPT groups. Results: The R-HPT group (8 men and 4 women) generally was older than the NR-HPT group (14 men and 8 women), but the age difference was not statistically significant. Patients in the R-HPT group had received radiotherapy (6.9 to 21.7 Gy) between 2 and 9 years of age for various diagnoses. Eight patients (67%) in the R-HPT group and 13 (59%) in the NR-HPT group had no symptoms of HPT. The rest of the patients in both groups had nonspecific symptoms, such as fatigue and dyspepsia. Four patients (18%) in the NR-HPT group had nephrolithiasis, and 3 (14%) had skeletal manifestations at initial assessment. Serum calcium, phosphorus, and parathyroid hormone levels and 24-hour urine calcium excretion were similar in both groups. Mean lumbar spine bone mineral density was lower in women in the R-HPT group than in those in the NR-HPT group, but the prevalence of osteoporosis did not differ significantly in the two study groups. Sestamibi scintigraphy accurately localized adenomas in both groups equally well (sensitivity >90%). In the R-HPT group, 11 patients had a single parathyroid adenoma and 1 had hyperplasia of all four parathyroid glands. In the NR-HPT group, 21 patients had a single parathyroid adenoma and 1 had parathyroid hyperplasia. In nine patients in the R-HPT group, ultrasonography showed thyroid nodules >1 cm. Pathologic examination of surgical specimens in the R-HPT group confirmed thyroid carcinoma in 11 patients (10 papillary and 1 follicular cancer); no patient in the NR-HPT group had thyroid cancer. Six weeks after thyroidectomy, patients with thyroid cancer received 131I (mean dose, 145 mCi), five of whom needed additional 131I treatments. Conclusion: Patients with a history of childhood neck irradiation who have HPT have a high likelihood of coexisting thyroid cancer. This observation may justify surgical exploration rather than vigilant follow-up in asymptomatic patients with primary HPT and coexisting thyroid nodules who have a history of radiation exposure.