BACKGROUND: Obesity is a risk factor for postmenopausal breast cancer, but the role of the timing and amount of adult weight change in breast cancer risk is unclear. METHODS: We prospectively examined the relations of adiposity and adult weight change to breast cancer risk among 99 039 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. Anthropometry was assessed by self-report in 1996. Through 2000, 2111 incident breast cancer cases were ascertained. RESULTS: Current body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), BMI at ages 50 and 35 years, and waist-hip ratio were associated with increased breast cancer risk, particularly in women not using menopausal hormone therapy (MHT). Weight gained between age 18 years and the current age, between ages 18 and 35 years, between ages 35 and 50 years, and between age 50 years and the current age was consistently associated with increased breast cancer risk in MHT nonusers (relative risk [RR], 2.15; 95% confidence interval [CI], 1.35-3.42 for a >/=50-kg weight gain between age 18 years and the current age vs stable weight) but not in current MHT users. Risk associated with adult weight change was stronger in women with later vs earlier age at menarche (RR, 4.20; 95% CI, 2.05-8.64 for >/=15 years vs RR, 1.51; 95% CI, 1.11-2.06 for 11-12 years; P = .007 for interaction). In MHT nonusers, the associations with current BMI and adult weight change were stronger for advanced disease than for nonadvanced disease (P = .009 [current BMI] and .21 [weight gain] for heterogeneity) and were stronger for hormone receptor-positive than hormone receptor-negative tumors (P < .001 for heterogeneity). CONCLUSION: Weight gain throughout adulthood is associated with increased postmenopausal breast cancer risk in MHT nonusers.