Based on the use of estrogen therapy/hormone therapy (ET/HT) in postmenopausal women and the prevalence of hypothyroidism in this population, it is estimated that approximately 5% of all postmenopausal women receive treatment with both ET/HT and thyroid hormone replacement. Hormone therapy generally refers to the combined use of estrogens and progestins, the latter administered on a continuous or intermittent basis. HT is indicated for the treatment of postmenopausal women with intact uteri, whereas ET is used in women who have had hysterectomies. Because of its hepatic first-pass effect, oral estrogen therapy, the most commonly used modality of ET/HT, raises the circulating levels of thyroxine-binding globulin (TBG), thereby increasing the bound fraction and decreasing the free (bioactive) fraction of circulating thyroxine (T(4)). As a consequence, oral ET/HT may increase the T(4) dosage requirements of women being treated for primary hypothyroidism as well as alter the pituitary-thyroid axis in euthyroid women. This paper reviews the potential interaction between ET/HT and thyroid hormone replacement based on the prevalence of their concomitant use, mechanistic aspects of the interaction, and recent clinical studies of the effects of oral ET in euthyroid and hypothyroid women. Other agents known to interact with thyroid hormone replacement, including soy supplements, are also reviewed. Because transdermal ET does not affect TBG levels and would not be expected to alter thyroid function, it may be a preferable modality for postmenopausal women who require concomitant treatment with ET/HT and T(4).