This research describes the effects of short-term elemental iodine (I2) and iodide (I−) replacement on thyroid glands and mammary glands of iodine-deficient (ID) Sprague-Dawley female rats. Iodine deficiency causes atypical tissue and physiologic changes in both glands. Tissue histopathology and the endocrine metabolic parameters, such as serum TT4, tissue and body weights, and vaginal smears, are compared. A moderate reduction in thyroid size from the ID control (IDC) was noted with both I− and I2, whereas serum total thyroxine approached the normal control with both I− and I2, but was lower in IDC. Thyroid gland IDC hyperplasia was reduced modestly with I2, but eliminated with I−. Lobular hyperplasia of the mammary glands decreased with I2 and increased with I− when compared with the IDC; extraductal secretions remained the same as IDC with I2, but increased with I−; and periductal fibrosis was markedly reduced with I2, but remained severe with I−. Thus, orally administered I2 or I− in trace doses with similar iodine availability caused different histopathological and endocrine patterns in thyroid and mammary glands of ID rats. The significance of this is that replacement therapy with various forms of iodine are tissue-specific.