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Notes: Abstract Background: The use of exogenous estrogen has been scrutinized as a risk factor for breast cancer formation. This prospective study addresses the relationship between the use of estrogen replacement therapy and the age of onset of breast cancer. In addition, an analysis of differences in pathological features of breast cancer between estrogen users and non-estrogen-users was evaluated. Methods: A total of 425 women (age, ≥ 50 years) were evaluated during a 4-year period (1994–1997). Data, including the age at diagnosis, method of detection, family history, use of estrogen therapy, and tumor ploidy, S-phase fraction, histological category, estrogen receptor positivity, and grade, were prospectively collected. Data from a control group of 657 women without a diagnosis of breast cancer were obtained from the Evanston Northwestern division of the Women’s Health Initiative. Significant associations between the use of estrogen and pathological parameters were determined using the χ2 test and t-test (P 〈 .05). Results: At the time of breast cancer diagnosis, 140 patients were currently receiving estrogen and 202 patients had no history of estrogen use. Eighty-three patients were excluded from analysis (76 patients had a history of previous but not current use of estrogen therapy, four women used only progesterone, and three patients provided incomplete information). There was no difference between patients with breast cancer using estrogen at the time of diagnosis and those with no history of estrogen use with respect to tumor size, age of menopause, family history, mammographic sensitivity, axillary lymph node status, and histological features. Women using estrogen at the time of diagnosis were younger at the time of breast cancer diagnosis, by an average of 5.1 years (61.3 years vs. 66.4 years, P 〈 .001). Women without a history of breast cancer who were receiving estrogen therapy were an average of 2.4 years younger (63.3 years vs. 65.7 years, P 〈 .001) than women without a history of breast cancer who were not receiving estrogen therapy. Patients with breast cancer receiving estrogen also tended to have more grade II tumors (45.9% vs. 36.5%, P = .045) and fewer grade III tumors (25.6% vs. 37.0%, P =.015), compared with women not receiving estrogen therapy at the time of their diagnoses. Estrogen receptor positivity was noted to be more frequent for estrogen users presenting with lobular carcinoma (85% vs. 76%, P =.042) and less frequent for estrogen users presenting with ductal carcinoma (72% vs. 85%, P = .003). Conclusions: A significantly earlier age of diagnosis for women receiving estrogen therapy suggests that exogenous estrogen may accelerate the pathogenesis of postmenopausal breast cancer. Estrogen therapy may also play a role in altering the grade and estrogen receptor positivity for certain histological types of breast cancer.