Obesity has been consistently associated with an increased risk of postmenopausal breast cancer in population-based studies. Conversely, obesity in such studies has been inversely associated with premenopausal breast cancer risk. In a report of data from two large chemoprevention trials, both of which enrolled women at a high risk of breast cancer, obesity was associated with only a modest, nonsignificantly increased risk of postmenopausal breast cancer and a surprising statistically significant 70% increased risk of premenopausal breast cancer (vs. normal weight). The discrepancies between these results and those from previous observational studies may be due to differences in study design and exposure ascertainment or due to inherent biologic differences whereby the obesity-breast cancer association differs for high-risk women in the clinical setting compared with general population, average-risk women in the observational setting.