The methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been linked to the risk of developing breast cancer. A meta-analysis of 18 case-control studies investigating the association between the C677T and the A1298C polymorphisms of the MTHFR gene and breast cancer (BC) was carried out. The meta-analysis included genotype data on 5467/7336 and 3768/5276 cases/controls for C677T and A1298C, respectively. In the meta-analysis, the consistency of genetic effects across different ethnicities and the effect of menopausal status for various genetic contrasts were investigated. The overall analysis for investigating the association between the C677T allele T and the risk of developing BC showed significant heterogeneity (p = 0.08, I2 = 34%) and non-significant association [odds ratio (OR) 1.02; 95% confidence interval (0.95-1.10)]. The allele contrast was not significant in Caucasians (nine studies) and in East Asians (four studies) [OR 1.03 (0.93-1.14) and OR 0.96 (0.81-1.15), respectively] or in pre-menopausal (five studies) and post-menopausal (four studies) groups [OR 1.10 (0.94-1.29) and OR 1.06 (0.95-1.18), respectively]. The genotype contrast of the homozygotes (TT vs CC) produced significant results only for pre-menopausal cases [OR 1.46 (1.05-2.03)]. The recessive model for allele T produced significant association only in pre-menopausal cases [OR 1.49 (1.09-2.03)]. The dominant model for the effect of allele T produced no significant results, overall and in each subgroup. For the A1298C polymorphism, all genotype contrasts showed lack of association, overall and in Caucasians. In summary, the accumulated evidence supports an association in pre-menopausal women. BC is a complex disease with multifactorial etiology, and therefore, case-control studies that investigate gene-environment interaction might elucidate further the genetics of the disease.