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The assumption that estradiol (E2) concentrations are reliably increased to therapeutic levels in postmenopausal women receiving hormone replacement therapy (HRT) has not been explicitly tested. Nor have factors that may modulate the E2 levels achieved been evaluated. The author examined E2 concentrations in a multiracial study population of 309 postmenopausal women treated with oral HRT and observed that 51.1% had achieved estradiol levels of at least 45 pg/ml (achievers). The odds of being an achiever were significantly elevated among non-Caucasian women by a HRT dose greater than 0.625 mg, current moderate drinking, and increasing duration of HRT use. The odds were significantly decreased by having a high school education or less and increasing time since last HRT dose. White postmenopausal women had significantly reduced odds of being an achiever, and both a dose of less than 0.625 mg and a dose equal to 0.625 mg significantly reduced the odds of being an achiever. Increasing body mass index and menopause duration were both associated with lower odds. This report demonstrates not only that women treated with HRT do not all achieve therapeutic levels of estradiol but also that factors can be identified that modulate the E2 concentration achieved in response to HRT administration.