In this systematic evidence review, we evaluate data on the relationship between the use of postmenopausal hormone replacement therapy (HRT) and the risk of breast cancer (BCA). The context of this review is in the overall evaluation of postmenopausal hormone replacement therapy as chemoprophylaxis for chronic conditions. The results from this report will be used as part of an overall report on the risks and benefits of hormone replacement therapy for postmenopausal women. Hormone replacement therapy is used in the United States and worldwide to treat symptoms of menopause and to prevent chronic conditions such as osteoporosis. It is one of the most commonly prescribed drugs in the U.S.; a recent survey in the U.S. of postmenopausal women ages 50 to 75 showed that nearly 38% of women were currently using estrogen or hormone replacement therapy (58.7% of those with prior hysterectomy and 19.6% without hysterectomy). A major and as yet unanswered clinical question is whether hormone replacement therapy increases a woman's risk of breast cancer. This issue is a critical one because the use of HRT is prevalent and because breast cancer is a relatively common disease, so that even a small increase in breast cancer in association with hormone use could significantly influence public health. The importance of endogenous estrogen in the development of breast cancer has been evaluated and confirmed in multiple studies of differing methodologies. Studies in animals have shown that breast cancer can be induced by the administration of estrogen. Among humans, some studies have shown that women with increased levels of circulating estrogen are at higher risk for the subsequent development of breast cancer. Other studies have had conflicting findings, and some have shown this relationship in postmenopausal women only. Reproductive events are important risk factors for breast cancer. Those shown to increase risk include early menarche and late menopause, both of which prolong exposure to higher levels of estrogen as well as other reproductive hormones. Other reproductive experiences, such as late age at first pregnancy and nulliparity, increase breast cancer risk. Oopherectomy among premenopausal women is protective against breast cancer, possibly because of reduced exposure to estrogen. Other risk factors also suggest an important role for estrogen in BCA development. In postmenopausal women, obesity, which correlates with increased estrogen levels, is also associated with an increased risk of BCA. Recent studies have also shown that increased bone density, possibly a reflection of lifetime estrogen exposure, is associated with increased rates of breast cancer. Finally, age-adjusted rates of increase in breast cancer incidence slow at menopause when estrogen levels fall. There are several critical key questions to consider when evaluating the research describing the role of exogenous estrogen or estrogen/progesterone in breast cancer development and prognosis. First, is either estrogen alone or estrogen with progesterone associated with a change in breast cancer mortality? Second, does short-term estrogen use increase the risk of breast cancer? The third question, which is most relevant to the use of estrogen to prevent chronic conditions, is whether long-term estrogen increases breast cancer risk. The fourth question, which reflects the current standard of practice, is whether the combination of estrogen and progesterone, either short-term or long-term, increases the risk of breast cancer. Fifth, is current use of estrogen or hormone replacement therapy associated with increased risk of breast cancer? Sixth, are there subpopulations of women who might be at increased risk of breast cancer when using HRT? Finally, because increased breast mammographic density is independently associated with an increase in breast cancer risk, as well as with decreased accuracy of mammography, does estrogen or estrogen/progestins change breast density?