Genome-wide association studies (GWAS) have identified common variants associated with breast cancer risk among women of European and Asian ancestries. To assess the generalizability across ethnic/racial populations of a risk score derived from genotyping 12 highly replicated breast cancer GWAS hits, we performed a case-control study (2224 cases and 2827 controls) nested in the Multiethnic Cohort (MEC) study, which was initiated in 1993-1996 and consists of subjects mainly from European-American, African-American, Native Hawaiian, Japanese and Latino populations. When viewed as a summary risk score, the total number of risk alleles carried by women was significantly associated with breast cancer risk overall (OR per allele, 1.09; 95% CI, 1.06-1.12; P=2.0 × 10(-10)) and in all populations except African-Americans, in which no significant association was observed (OR, 1.03; 95% CI, 0.98-1.08). In aggregate, the number of risk alleles is strongly associated with breast cancer risk in all populations studied except African-Americans. These results emphasize the need for large-scale association studies of multiple racial/ethnic groups for discovery and characterization of risk alleles relevant to all populations in the United States.