Abnormal calcitonin secretion provides a reliable marker for the presence of medullary carcinoma of the thyroid (MCT) and its precursor form, C-cell hyperplasia (CCH). Since this tumor may be transmitted by a dominant autosomal gene, the coincidence of a sensitive marker and an easily identified "at risk" population affords an unusual opportunity for cancer prophylaxis. To evaluate the specificity and sensitivity of provocative tests used for detection of C-cell disease, we have compared the calcitonin (hCT) responses to calcium (3 mg/kg body weight over 10 minutes intravenously), pentagastrin (0.5 microgram/kg body weight), and injection of calcium (1.0 mg/kg body weight) plus pentagastrin (0.25 microgram/kg body weight) over 60 seconds in 13 patients with subsequently proven MCT or CCH and in 31 normal volunteers. The ranges of hCT observed in normals after injection of pentagastrin and combined calcium and pentagastrin were lower than those seen in all nine patients with MCT. One subject, the only MCT patient with normal basal hCT values, had a normal response to calcium whereas all others achieved supranormal levels. Basal hCT levels were normal in the four patients with CCH but the hCT response to calcium was to a value in excess of 300 pg/mL, a level exceeded by only 3 of 31 normal subjects; the hCT response to pentagastrin in CCH and in normal subjects was indistinguishable. Combined calcium and pentagastrin administration was associated with abnormal hCT responses in two of the CCH patients and in the MCT patient with a normal response to calcium.(ABSTRACT TRUNCATED AT 250 WORDS)