Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularly occult familial MTC. In previous radioimmunoassays of calcitonin, polyclonal antibodies were used. Here we evaluate a new two-site immunoradiometric assay (IRMA) of calcitonin based on use of monoclonal antibodies. We assayed samples from healthy subjects, patients with renal failure, and subjects from families affected by MTC. Basal values for healthy subjects were all less than 10 ng/L. Renal failure is associated with increased basal CT. The CT peak under pentagastrin stimulation in healthy patients was less than 30 ng/L. In familial screening, basal values greater than 10 ng/L or peak values greater than 30 ng/L correspond to subjects with histologically confirmed MCT or micro-MCT. Polyclonal RIA performed in the same subjects failed to detect the moderate increase of CT that IRMA demonstrated. Preliminary results indicate that this new method may allow earlier detection of CT increase and thus improved diagnosis of MCT, particularly in familial screening. Monitoring surgical patients could also be improved by this new assay.