To examine effects of body size change on postmenopausal breast cancer, the authors conducted a population-based case-control study among 990 cases and 1,006 controls participating in the Long Island Breast Cancer Study Project in 1996-1997. Women who had gained more than 15 kg (33 pounds) since age 20 years were at a 1.6-fold increased risk of breast cancer (95% confidence interval (CI): 1.11, 2.26) relative to their counterparts with stable (+/-3 kg) weight. Subjects who had gained more than 11 kg (24 pounds) during the peri- and postmenopausal years (since age 50 years) had 1.62 times the risk of breast cancer of those whose weight remained unchanged during this time period. This effect of peri- and postmenopausal body size gain was present only among never users of hormone replacement therapy (odds ratio (OR) = 2.02 (95% CI: 1.35, 3.02) as opposed to 0.81 (95% CI: 0.43, 1.53) for ever users; multiplicative interaction: p < 0.01) and was more pronounced among women with estrogen receptor-positive/progesterone receptor-positive breast cancer (OR = 2.17, 95% CI: 1.38, 3.42). Weight loss over the lifetime was associated with decreased risk of postmenopausal breast cancer (OR = 0.55, 95% CI: 0.32, 0.96). These results add to the literature by focusing on the perimenopausal weight trajectory and support efforts urging women to avoid weight gain as they age.