Abstract Hispanics in the U.S. Southwest have genetic ancestry from Europeans and from American Indians, two groups with markedly different breast cancer incidence rates. Genetic admixture may therefore bias estimates of associations between candidate cancer susceptibility genes and breast cancer in Hispanics. We estimated genetic admixture using 15 ancestry-informative markers for 1,239 Hispanics and 2,505 non-Hispanic Whites in a breast cancer case-control study in the Southwest, the Four Corners Study. Confounding risk ratios (CRR) were calculated to quantify potential bias due to admixture. Genetic admixture was strongly related to self-reported race and ethnic background (P < 0.0001). Among Hispanic controls, admixture was significantly associated with allele frequency for 5 of 11 candidate gene single nucleotide polymorphisms (SNP) examined. Hispanics in the highest versus the lowest quintile of American Indian admixture had higher mean body mass index at age 30 years (25.4 versus 23.6 kg/m2; P = 0.003), shorter mean height (1.56 versus 1.58 m; P = 0.01), higher prevalence of diabetes (14.8% versus 7.2%; P = 0.04), and a larger proportion with less than a high school education (38.5% versus 23.2%; P = 0.001). Admixture was not associated with breast cancer risk among Hispanics (P = 0.65). CRRs for potential bias to candidate SNP-breast cancer risk ratios ranged from 0.99 to 1.01. Thus, although genetic admixture in Hispanics was associated with exposures, confounding by admixture was negligible due to the null association between admixture and breast cancer. CRRs from simulated scenarios indicated that appreciable confounding by admixture would occur only when within-group candidate SNP allele frequency differences are much larger than any that we observed. (Cancer Epidemiol Biomarkers Prev 2007;16(1):142–50)