Several studies using families with multiple occurrences of breast cancer have provided evidence for a very high lifetime penetrance in carriers of BRCA1 or BRCA2 mutations. However, there are reasons to suspect that the estimates of penetrance from studies of cancer families may be inflated. Access to the genotypes of incident cases of breast cancer in three hospitals and from a large series of unaffected survey participants provided the basis for direct estimation of the age-specific relative risks attributable to these mutations, and the resulting lifetime penetrance, without any reference to familial aggregation of cancer. Cases were identified from incident series of Jewish patients treated for primary breast cancer at the three hospitals. Control data were obtained from the large series of Jewish women recruited in the Washington, D.C., area by investigators at the National Cancer Institute and limited to 3434 women with no previous history of breast or ovarian cancer. All subjects were genotyped for the three mutations that are relatively common in Ashkenazi Jews, namely 185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2. For BRCA1, the relative risks of breast cancer were estimated to be 21.6 in women under 40 years of age, 9.6 in women 40-49 years of age, and 7.6 in women > or = 50 years of age. On the basis of these estimates, the penetrance of breast cancer at age 70 among BRCA1 mutation carriers is estimated to be 46% (95% confidence, 31%-80%) rising to 59% (95% confidence, 40%-93%) at age 80. For BRCA2, the relative risks in the same three age categories were estimated to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance at age 70 of 26% (95% confidence, 14%-50%) rising to 38% (95% confidence, 20%-68%) at age 80. The lifetime risk of breast cancer in Jewish women who are mutation carriers estimated via this approach is substantially lower than the reported lifetime risks estimated using multiple-case families. The risks appear to be different for carriers of BRCA1 and BRCA2 mutations.