Normal C-cells are classically concentrated between the upper and middle thirds of each thyroid lobe and account for less than 1% of the thyroid gland volume. C-cell hyperplasia (CCH), defined as the presence of at least 3 low-power magnification (x100) microscopic fields containing more than 50 C-cells and at least 40 cells/cm2 was first described in a familial context of MEN2. It was then observed in many other conditions, especially in association with chronic lymphocytic thyroiditis or with thyroid tumors other than medullary thyroid carcinoma (MTC). In members of a MEN2 family, carrying a RET mutation, CCH is constant and associated with micro-MTC. At least 20% of patients with chronic lymphocytic thyroiditis or with a thyroid tumor other than MTC have CCH that, in a few cases, is associated with hypercalcitoninemia. 20 % normal subjects meet quantitative criteria of CCH. Patients belonging to a MEN2 family, without a RET mutation but presenting hypercalcitoninemia, could belong to this group. HCC appears to be a pre-neoplastic condition only in patients carrying a RET mutation. Under other circumstances, HCC may be either a reactive or even a normal condition.