We have earlier demonstrated the role of aberrant one‐carbon metabolism in the etiology of breast cancer. In the current study, we examine the clinical utility of these factors in predicting the subtype of breast cancer and as indicators of disease progression. Polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) and PCR–amplified fragment length polymorphism (AFLP) approaches were used for genetic analysis. Plasma folate and homocysteine were measured using Axsym folate kit and reverse phase HPLC, respectively. Multiple linear regression models were used to test the predictability of disease progression. Luminal A subtype was associated with late age of onset, higher body mass index and lack of family history of breast cancer. Thymidylate synthase (TYMS) 5′‐UTR 28 bp tandem repeat (OR: 2.09, 95% CI: 1.05–4.16) and methylene tetrahydrofolate reductase (MTHFR) C677T (OR: 4.10, 95% CI: 1.40–11.95) were strongly associated with Luminal B. Reduced folate carrier (RFC1) G80A (OR: 2.92, 95% CI: 1.22–6.97) and methionine synthase (MTR) A2756G (OR: 4.71, 95% CI: 1.66–13.31) polymorphisms were associated with LuminA‐HH subtype while MTHFR C677T showed association with HER‐enriched (OR: 30.41, 95% CI: 6.47–142.91). Cytosolic serine hydroxymethyltransferase (cSHMT) conferred protection against basal‐like breast cancer (OR: 0.47, 95% CI: 0.22–0.98). HER‐enriched and basal‐like subtypes showed positive association with familial breast cancer and inverse association with plasma folate. Hyperhomocysteinemia was observed in Luminal B and basal‐like subtypes. Multiple linear regression models of aberrant one‐carbon metabolism were found to be moderate predictors of breast cancer grade (area under the receiver operating characteristic curve, C = 0.72, 95% CI: 0.58–0.87, P = 0.008). To conclude, aberrations in one‐carbon metabolism predict the subtype of breast cancer and disease progression. © 2011 Wiley Periodicals, Inc.