Abstract Background: Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight. Methods: We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies. Results: We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk. Conclusion: The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist. Impact: The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 21(3); 552–6. ©2012 AACR.