Calcitonin gene-related peptide (CGRP) is a recently discovered peptide whose existence was first predicted following sequence analysis of the rat calcitonin gene. In the present study, plasma levels of CGRP were measured in patients with medullary thyroid carcinoma, both basally and following calcium or pentagastrin stimulation. Using a sensitive radioimmunoassay for CGRP, 19 of 21 patients with medullary thyroid carcinoma had elevated plasma levels of immunoreactive CGRP (median value 114 pmol/l) while 23 normal subjects had plasma CGRP levels below the detection limit of the assay (less than 10 pmol/l). Calcium or pentagastrin infusion in medullary thyroid carcinoma patients were potent stimuli to CGRP release, increasing plasma levels two- to five-fold. Chromatographic characterization using high pressure liquid chromatography of the CGRP immunoreactivity in plasma from two patients with medullary carcinoma of the thyroid demonstrated the presence of two molecular forms, neither of which co-eluted with synthetic human CGRP. The role of CGRP in the pathophysiology of medullary thyroid carcinoma is not clear but it may contribute to some of the clinical features associated with the disease. Furthermore, measurement of CGRP in conjunction with calcitonin could help in determining the prognosis of these patients.