Abstract Methylenetetrahydrofolate reductase(MTHFR) is a key enzyme in folate metabolism that is critical for DNA methylation, synthesis and repair. Since genetic polymorphisms may modify the efficiency of this enzyme, we tested the hypothesis that MTHFR modifies breast cancer (BC) survival using data from the Health, Eating, Activity and Lifestyle (HEAL) Study for 772 incident primary invasive cases (Stage I-IIIA). Over the 5-year follow-up there were 50 women diagnosed with a recurrence and 39 with a new primary. Over 7-years of follow-up, there were 160 deaths; 97 due to BC. In Cox proportional-hazards analysis, carriers of variant alleles of MTHFR polymorphisms, C677T (HR = 0.76, 95% confidence interval CI: 0.51, 1.14) and A1298C (HR = 0.66, 95% CI: 0.44, 1.00), had reduced mortality rates, adjusting for ER status and stage. In women with more severe disease who received chemotherapy, the HR was 5.6(95% CI: 2.8-10.9) for those without the T allele, and 4.3(95% CI: 2.1-9.1) for those with it present (p = 0.09) compared to those without the T allele and no chemotherapy treatment (Table 1). No interaction with chemotherapy was observed for A1298C. C677T may modify the association of chemotherapy in predicting BC survival. There is strong linkage disequilibrium between C677T and A1298C (Lewontin's D’ = 0.94) suggesting two different inheritance patterns; however, recombination between them is documented to be rare. These results should be explored further in clinical populations. Study of interactions with other genes in the folate metabolism pathway (BHMT, TS, MTR, MTRR, SHMT) with BC survival is under investigation Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2750. doi:10.1158/1538-7445.AM2011-2750