Adenomatous polyposis coli (APC) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of Apc, we have investigated Apc (1638T/1638T) mice, which express a truncated Apc that lacks the C-terminal domain. Apc (1638T/1638T) mice are tumor free and exhibit growth retardation. In the present study, we analyzed the morphology and functions of the thyroid gland in Apc (1638T/1638T) mice. There was no significant difference in the basal concentration of serum thyroid hormones between Apc (1638T/1638T) and Apc (+/+) mice. Thyroid follicle size was significantly larger in Apc (1638T/1638T) mice than in Apc (+/+) mice. The extent of serum T4 elevation following exogenous thyroid-stimulating hormone (TSH) injection was lower in Apc (1638T/1638T) mice than in Apc (+/+) mice. TSH also induced a greater reduction in thyroid follicle size in Apc (1638T/1638T) mice than in Apc (+/+) mice. Analyses using immunohistochemistry and electron microscopy indicated that follicular epithelial cells in Apc (1638T/1638T) mice had an enlarged rough endoplasmic reticulum of irregular shape. These results suggest that the C-terminal domain of Apc is involved in thyroid morphology and function.