The quantitative analysis of immunoreactive calcitonin (iCT) is the assay of choice for diagnosis and follow-up of patients with medullary thyroid carcinoma (MTC). However, in a small percentage of patients with MTC or C cell hyperplasia (CCH), basal and stimulated iCT levels may not be significantly elevated. In these patients, calcitonin gene-related peptide (CGRP) radioreceptor assay (RRA) can be used complementary to immunoassay for CT (or katacalcin) for prompt diagnosis of MTC and CCH. CGRP RRA is a robust, rapid, sensitive, and specific determinant of "receptor-recognized" CGRP (RR-CGRP; intact molecule of CGRP) either in plasma or in tissue extracts. Plasma RR-CGRP levels rose > 100% 2-5 minutes after stimulation with intravenous pentagastrin (calcium or oral alcohol) (p < 0.001), whereas iCGRP levels were raised to a lesser degree (p < 0.01). In six patients who had a false positive iCT response after pentagastrin or had raised basal iCT levels measured with a two-site immunoradiometric assay, RR-CGRP showed only a minimal change. On the other hand, in patients with CCH (true positive, n = 8), iCT was increased by only 40% after pentagastrin but RR-CGRP levels rose by 140% (p < 0.001). No change in iCT or RR-CGRP levels in plasma were detected in healthy normal volunteers after administration of pentagastrin. Therefore, in addition to the plasma iCT levels, RR-CGRP would resolve some of the difficult diagnostic problems associated with MTC and likely improve the specificity and sensitivity of identifying CCH.