BACKGROUND/AIM: Residual or recurrent medullary thyroid carcinoma (MTC) after thyroidectomy is diagnosed by elevated serum calcitonin (CT) levels. However, in minimal residual MTC or C-cell hyperplasia (CCH), where imaging studies are often negative, basal CT levels are frequently normal and CT stimulation tests are required. We aimed to compare CT stimulation tests with calcium, pentagastrin and their combination in identifying minimal residual MTC and CCH.MATERIAL AND METHODS: We studied 10 post-thyroidectomy patients with MTC and 20 first-degree relatives of the patients who had no clinically apparent MTC. We performed 54 combined (calcium plus pentagastrin) stimulation tests, 35 calcium stimulation tests and 26 pentagastrin stimulation tests.RESULTS: Basal CT levels were abnormal (≥500 pg/ml) in 4 patients with apparent metastatic disease (Group 1A) and in 2 patients with minimal residual disease (Group 1B) but were normal (0-300 pg/ml) in 4 patients with no residual disease (Group 1C) and in the relatives (Group 2). In Groups 1A, 1B and 1C, maximal elevation in CT levels was greater after the combined stimulation test than after calcium or pentagastrin tests. The combined stimulation test induced the greatest increases (920, 700 and 706 pg/ml, respectively) in 3 relatives (Group 2); CCH was confirmed histologically in these patients. Side-effects were mild, short-lasting and of similar intensity and duration during all tests.CONCLUSIONS: Patients with subclinical MTC (minimal residual or recurrent MTC) or their relatives (with CCH) usually have normal basal CT levels and stimulation tests are necessary. Combined test represents the most sensitive and safe stimulation test for the diagnosis of subclinical hypercalcitonemia.