Multiple gland parathyroid disease is the pathological finding in primary hyperparathyroidism (HPT) in about 10% to 20% of all patients and in approximately a third of all patients with persistent or recurrent disease. The variability of multiple gland disease spans from 2 adenomas to diffuse hyperplasia in patients with multiple endocrine neoplasia type 1. This variability calls into question the proposed common pathophysiologic background in all of these cases. As primary treatment of multiple gland primary HPT, subtotal parathyroidectomy and thymectomy or total parathyroidectomy and heterotopic autotransplantation including thymectomy can be equally advocated. Recurrent hyperparathyroidism frequently occurs in cases of diffuse parathyroid hyperplasia. This must be considered especially in patient follow up and before each surgical procedure. Thus, a defined but adaptable therapeutic regimen might prevent permanent hypoparathyroidism and persistent hyperparathyroidism.