A 63-year-old man with a goiter and primary hypothyroidism due to Hashimoto's thyroiditis was found to have hypercalcitonemia and, though hypothyroid, markedly elevated serum total and free T3 levels. The latter findings were attributable to circulating T3 autoantibodies and interference with radioimmunoassay. An infusion of calcium and pentagastrin resulted in abnormal increases in serum calcitonin levels. Because there was no evidence of a nonthyroidal cause for the hypercalcitonemia, the patient had a total thyroidectomy. Pathological examination of the thyroidectomy specimen revealed typical Hashimoto's thyroiditis and extensive C-cell hyperplasia symmetrically distributed throughout the upper and middle thirds of each lobe. The C cells stained strongly with immunoperoxidase stains for calcitonin, chromogranin, and CEA using absorbed polyclonal anti-CEA antibody. Less extensive staining for CEA was obtained using the monoclonal antibodies for CEA, 374/14, 250/183, and 431/31; only a few reactive cells were noted using 431/31. Postoperatively, serum calcitonin levels fell to normal and did not rise with a repeat calcium-pentagastrin infusion test. This patient appears to be the first instance of C-cell hyperplasia associated with Hashimoto's thyroiditis, while elsewhere an association with medullary thyroid carcinoma has been reported. These observations raise questions regarding a possible pathogenetic relationship between Hashimoto's thyroiditis and C-cell neoplasia.