We have sought to determine whether medullary thyroid carcinoma (MTC) released calcitonin gene-related peptide (CGRP) in vivo. MTC cells were inoculated from tissue culture into eight Wag-Rij rats. One month later blood was drawn before and after the intravenous injection of calcium, and plasma levels of CGRP and calcitonin (CT) levels in that blood were determined by radioimmunoassay. The tumor was examined for content of CGRP and of CT by means of radioimmunoassay and immunocytochemistry. The tumor was divided and portions were passed to another eight rats. One month later, the studies were repeated. The tumor was passed two additional times (four passages in all). Controls consisted of non-tumor-bearing Wag-Rij rats. Basal levels of plasma CGRP in control rats (7 +/- 1 ng/ml) were unaffected by calcium stimulation. In tumor-bearing rats, the plasma CGRP level, which was initially slightly elevated (15 +/- 7 ng/ml), rose progressively with passages to 279 +/- 79 ng/ml in the third passage and fell to normal values at the end of passage four. Hypercalcemia had no effect on plasma CGRP levels in tumor-bearing rats but did stimulate the release of CT in both control and tumor-bearing rats, although it is not clear whether this release was from the tumor or from normal thyroid parafollicular cells in these tumor-bearing rats. We conclude that rat MTC synthesizes and releases CGRP but, unlike CT, CGRP appears unresponsive to calcium stimulation.