With few exceptions, most epidemiologic studies do not show an excess relative risk of breast cancer associated with menopausal estrogen therapy. Other studies show a relationship of breast cancer to obesity, which is characterized by increased endogenous estrogen production. This study explored the possibility of an interaction between ponderosity and exogenous estrogen use in a case-control study of 113 postmenopausal breast cancer patients and pair-matched hospital control subjects. In this series, neither menopausal estrogen use nor relative weight were significantly associated with breast cancer risk. However, among estrogen users, the relative risk of breast cancer was strikingly influenced by the ponderosity of the subjects; the relative risk was 0.41 for women whose relative weight was less than the median, compared with 1.29 for those whose relative weight exceeded the median. The mean age was also examined at diagnosis in order to explore the potential of exogenous estrogen as a tumor promotor. The mean age at breast cancer diagnosis in estrogen users, 58.1 years, was significantly lower than in nonusers, 63 years. A significant linear relationship was found between age at diagnosis and body weight among estrogen users. Estrogen-treated women in the lowest tertile of body weight had the diagnosis of breast cancer made seven years earlier than those in the highest tertile of weight. There was no significant difference in the distribution of clinical stages at diagnosis between estrogen users and nonusers. These data suggest that relative body weight is an important modifier of the effect of exogenous estrogens on breast cancer biology.