The histone protein family member X (H2AFX) is important in maintaining chromatin structure and genetic stability. Genetic variants in H2AFX may alter protein functions and thus cancer risk. In this case-control study, we genotyped four common single nucleotide polymorphisms (i.e., -1654A > G [rs643788], -1420G > A [rs8551], and -1187T > C [rs7759] in the H2AFX promoter region and 1057C > T [rs7350] in the 3' untranslated region (UTR)) in 467 patients with sporadic breast cancer and 488 cancer-free controls. All female subjects were non-Hispanic whites aged T polymorphism. Therefore, we believe that H2AFX promoter polymorphisms may contribute to the etiology of sporadic breast cancer in young non-Hispanic white women. Larger association studies and related functional studies are warranted to confirm these findings.