Chronic lithium therapy in patients with affective psychiatric disorders has been implicated as the cause of hypercalcemia and primary hyperparathyroidism. Our objective was to evaluate whether primary hyperparathyroidism was caused by an adenoma or four-gland hyperplasia. The medical records of 15 patients with affective psychiatric disorders who were treated with chronic lithium therapy from 1982 to 1997, all of whom were operated on for primary hyperparathyroidism, were reviewed. Data on age, symptoms, duration of lithium therapy, pre- and postoperative calcium levels, and parathyroid hormone levels were collected. Parathyroid histology for each patient was independently and blindly reviewed. The mean age was 58 +/- 10 years, the mean duration of lithium therapy 10.7 +/- 6 years, and the mean preoperative calcium level 11.7 +/- 0.5 mg/dl. All patients underwent bilateral neck exploration with selective resection of enlarged glands. Of the 15 patients, 14 (92%) had adenomas (11 single, 3 double), and 1 (8%) had four-gland hyperplasia. All patients were rendered eucalcemic, with a postoperative calcium level of 9.2 +/- 0.5 mg/dl ( p < 0.005). All patients resumed their lithium therapy, with 1 of 15 patients developing recurrent hyperparathyroidism 2 years following the first operation; this patient required reexploration, at which time an adenoma was resected. In our experience hyperparathyroidism in patients who have undergone prolonged therapy with lithium is associated with a high incidence of parathyroid adenomas versus four-gland hyperplasia. This suggests that lithium selectively stimulates growth of parathyroid adenomas in susceptible patients, who are best treated with adenoma excision rather than subtotal parathyroidectomy.