Noninsulin-dependent diabetes mellitus and postmenopausal breast cancer share a number of risk factors, including obesity, increased waist-to-hip ratio, and a positive family history. If risk for these diseases is mediated through a familial tendency for abdominal obesity, then one might expect to see familial clustering of both diseases. We analyzed data from a prospective cohort study of 41,837 Iowa women age 55-69 years. Diabetes was not associated with incidence of breast cancer [relative risk (RR) = 0.97]. The association between family history of breast cancer and breast cancer incidence, however, was slightly modified by individual history of diabetes: a positive family history of breast cancer in the absence of baseline diabetes was associated with a relative risk of 1.36 [95% confidence interval (CI) = 1.08-1.70], whereas the presence of both factors was associated with a RR of 1.87 (95% CI = 0.93-3.76). Adjustment for waist-to-hip ratio greatly diminished this difference. Conversely, a family history of breast cancer was associated with a RR of 5-year diabetes mortality of 1.94 (95% CI = 1.17-3.24) that persisted after stratification by tertile of waist-to-hip ratio. No clear association of family history of breast cancer and waist-to-hip ratio for self-reported diabetes incidence was evident. These data are indicative of a complex interrelation between waist-to-hip ratio, familial predisposition, diabetes, and breast cancer.