In order to elucidate the functional significance of somatostatin in thyroid C cells, the alterations of immunoreactive somatostatin in the cells were investigated under various experimental conditions, i.e., hypercalcemia, hypocalcemia, and antithyroid drug treatment. Guinea pigs and rabbits, in which almost all C cells reveal the intense immunoreaction for somatostatin in addition to calcitonin, were used as experimental animals. After chronically induced hypercalcemia, somatostatin immunoreactivity conspicuously diminished coinciding with the decrease of calcitonin; somatostatin as well as calcitonin was responsive to induced hypercalcemia. After hypocalcemic tetany induced by injection of Escherichia coli L-asparaginase, C cells exhibited very intense immunoreactions for both calcitonin and somatostatin. After chronic treatment of ethylenethiourea, immunoreaction of somatostatin in C cells was the same as that of calcitonin. That is, when immunoreactivity for calcitonin remained unchanged, immunoreactivity for somatostatin was also intensive. However, when immunoreaction of calcitonin became very weak, the reaction of somatostatin was also weak. Thus, in all experimental conditions examined the alterations of immunoreactive somatostatin in C cells completely coincided with those of calcitonin. It seems likely that somatostatin in thyroid C cells exerts the synergistic effect on calcitonin action.