A family history of breast cancer potentially identifies women at high risk for whom mammography may be especially valuable. The authors examined the association of fatal breast cancer and family history in a large, prospective study of US adults. After 6 years of follow-up, 880 cases of fatal breast cancer were observed in a cohort of 604,412 women who were cancer free at interview in 1982. Cox proportional hazards modeling found that a family history of breast cancer in a mother or sister was significantly related to fatal breast cancer risk (rate ratio = 1.59, 95% confidence interval (CI) 1.29-1.95). The association was greatly modified by age; the rate ratio was 4.91 (95% CI 1.39-17.3) in women aged < 40 years at enrollment compared with 1.28 (95% CI 0.78-2.11) in women aged > or = 70 years. Among young (aged < 50 years) women, the risk associated with a positive family history was greatest if the relative was also young at the time of diagnosis (rate ratio = 5.22, 95% CI 3.00-9.11). These associations were not altered in multivariate analyses controlling for known breast cancer risk factors. In the authors' data, family history is strongly predictive of early fatal breast cancer, particularly when the disease is diagnosed before age 50 in the relative. Women with a family history of early breast cancer should receive special instructions regarding mammography and early detection.