PURPOSE: Hormone replacement therapy (HRT) has been associated with an increased risk for breast cancer. Cancers in women who undergo HRT are often less advanced, and a lower mortality has been reported in those who use HRT vice nonusers. We sought to explain this by a comparison of indicators of tumor aggressiveness in patients who received HRT with those in patients who did not. METHODS: A population-based cohort of 370 postmenopausal women with breast cancer were interviewed for the use, type, and duration of HRT. Clinical variables and indicators of tumor aggressiveness (nuclear grade, hormone receptors, c-erb B2 overexpression, tumor size, lymph node) were analyzed. RESULTS: Breast tumors from 268 HRT patients were smaller (P=0.001), had less involved axillary lymph nodes (P=0.0), and had a lower overexpression of c-erb B2 (P=0.047) than the tumors from 102 non-recipients. These differences persisted after adjustments for age at diagnosis and screening with mammography by multiple logistic regression. No significant differences were observed in estrogen (ER) or progesterone receptor content (PR) or, nuclear grade. Neither the type of HRT (estrogen versus combination of estrogen and progesterone), nor the duration of HRT was not associated with the tumor size or with the involvement of lymph nodes. The use of HRT was significantly associated with a longer metastasis free survival in women with breast cancer (P=0.028), but was not associated with longer overall survival. The use of HRT was not significantly associated with longer overall survival or with a longer metastasis free survival after adjustment for T-stage, N-stage, age at diagnosis or screening mammography. CONCLUSION: The results indicate that breast cancer in women who receive HRT is biologically less aggressive than those without previous HRT. This may at least partly explain why breast cancer in HRT users has a more favorable clinical course.