We evaluated the impact of a family history of breast/ovarian cancer on the risk of secondary leukemia following breast cancer. At the Geneva cancer registry, we identified 4,397 patients diagnosed with invasive breast cancer between 1990 and 2004. Patients were followed up for leukemia until the end of 2005. Family history was categorized as positive in patients with >or=1 first- or second-degree relative with breast/ovarian cancer. We compared leukemia rates in patients with positive and negative family histories with those expected in the general population, generating standardized incidence ratios (SIRs). With Cox regression analysis, we calculated adjusted risks of secondary leukemia in patients with familial risks compared to those without it. Breast cancer patients had a significantly increased risk of secondary acute leukemia (SIR 3.2, 95% CI: 1.2-6.9) but not of chronic leukemia (SIR 1.6, 95% CI: 0.6-3.5). Among patients with a positive family history (n = 1.125, 25.6%), the SIRs were 5.7 (95% CI: 1.2-16.6) for acute and 5.2 (95% CI: 1.4-13.3) for chronic leukemia. Among breast cancer patients, family history was independently associated with leukemia [adjusted hazard ratio (HR(adj)) of 3.2, 95% CI: 1.1-9.2, among patient with vs. without family history]. The effect of family history was stronger for chronic leukemia (HR(adj): 11.6, 95% CI 1.3-104.7) than for acute leukemia (HR(adj) 1.6, 95% CI: 0.4-6.6). Breast cancer patients with a family history of breast/ovarian have an increased risk of secondary leukemia, both compared to the general population as well as to breast cancer patients without family histories. This excess risk is largely due to the increased risk of secondary chronic leukemia.