Beyond the current emphasis on body mass index (BMI), it is unknown whether breast cancer risk differs between metabolically healthy and unhealthy normal weight or overweight/obese women. The Sister Study is a nationwide prospective cohort study. Data came from 50,884 cohort participants aged 35 to 74 years enrolled from 2003 through 2009. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for breast cancer risk. Metabolic abnormalities considered included: high waist circumference (88 cm); elevated blood pressure (130/85 mm Hg or antihypertensive medication); previously diagnosed diabetes or antidiabetic drug treatment; and cholesterol-lowering medication use. During follow-up (mean, 6.4 years), 1,388 invasive breast cancers were diagnosed at least 1 year after enrollment. Compared to women with BMI <25 kg/m(2) with no metabolic abnormalities (metabolically healthy normal weight phenotype), women with a BMI <25 kg/m(2) and 1 metabolic abnormality (metabolically unhealthy, normal weight phenotype) had increased risk of postmenopausal breast cancer (HR=1.26, 95% CI: 1.01-1.56), as did women with a BMI 25 kg/m(2) and no metabolic abnormalities (metabolically healthy overweight/obese phenotype) (HR=1.24, 95% CI: 0.99-1.55). Furthermore, risk of postmenopausal breast cancer was consistently elevated in women with normal BMI and central obesity (normal weight central obesity phenotype) regardless of the criterion used to define central obesity, with HR for waist circumference 88 cm, waist circumference 80 cm, and waist-hip ratio 0.85 of 1.58, 95% CI: 1.02-2.46; 1.38, 95% CI: 1.09-1.75; and 1.38, 95% CI: 1.02-1.85, respectively. There was an inverse association between premenopausal breast cancer and metabolically healthy overweight/obese phenotype (HR=0.71, 95% CI: 0.52-0.97). Our findings suggest that postmenopausal women who are metabolically unhealthy or have central adiposity may be at increased risk for breast cancer despite normal BMI. What's new? Does the association between metabolic factors such as hypertension, diabetes, high cholesterol, or central obesity and risk of breast cancer differ for normal weight and overweight/obese women? In this study, the authors found that normal weight postmenopausal women who are metabolically unhealthy may have an increased risk of breast cancer despite normal body mass index, as do overweight and obese women who are metabolically healthy. These findings suggest that targeting metabolic abnormalities may provide additional targets for prevention strategies to reduce breast-cancer risk.