Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries1, not all children have benefited equally from this progress2. Ethnic differences in survival after childhood ALL have been reported in many clinical studies3-11, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians3-5. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important 4,12. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse. © 2011 Nature America, Inc. All rights reserved.