The effect of aging on the formation of C cell follicles was examined in the thyroid gland of guinea pigs at various ages ranging from 1 to 29 months. The C cell follicles were demonstrated with the immunoperoxidase methods by using anticalcitonin and antisomatostatin antisera and with PAS reaction. They were already detected in 1-month-old guinea pigs but in low number. Thyroid glands from 1- to 14-month-old animals contained only a small number of C cell follicles and did not reveal the age-related increase. In aged guinea pigs (20- to 29-month-old), a dramatic increase of C cell follicles was found, about 13 times as high as the number of other age groups. The C cell follicles through all age groups were present in large clusters of C cells. In the aged guinea pigs, nodular large aggregates of C cells regarded as C cell hyperplasia occurred and numerous C cell follicles were formed in the large cell aggregates. Thus, the conspicuous increase of C cell follicles in aged animals was associated with a proliferative abnormality of C cells. The C cells forming follicles showed moderate to weak immunoreactivity for calcitonin, whereas they showed very intense immunoreactivity for somatostatin. In addition, the colloidlike and flocculent materials stored in the follioular lumina, which were consistently PAS-positive, were weakly immunoreactive to somatostatin but nonreactive to calcitonin.