The authors investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating oxidative stress in sporadic breast cancer. PCR-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) methods were used for genetic analysis in 222 sporadic breast cancer cases and 235 controls. Standardized food frequency questionnaire was used for dietary micronutrient assessment. 8-oxo-2'-deoxyguanosine (8-oxodG), folate, and estradiol were estimated using commercial ELISA kits. Reverse-phase HPLC coupled with fluorescence detector was used for plasma homocysteine analysis. Total glutathione was estimated using Ellman's method. Reduced folate carrier 1 (RFC1) G80A and methylenetetrahydrofolate reductase (MTHFR) C677T were associated with risks of 1.34 (95% CI 1.01-1.79)- and 1.84 (95% CI 1.14-3.00)-folds, respectively, for sporadic breast cancer while cytosolic serine hydroxymethyl transferase (cSHMT) C1420T was associated with reduced risk (OR 0.71, 95% CI 0.53-0.94). Significant increase in plasma 8-oxo-2'-deoxyguanosine (P < 0.004) and homocysteine (P < 0.0001); and significant decrease in total glutathione (P < 0.01) and dietary folate (P = 0.006) was observed in cases than in controls. Oxidative DNA damage showed direct association with menopause (P = 0.02), RFC1 G80A (P < 0.05) and homocysteine (P < 0.0001); and inverse association with dietary folate (P < 0.0001), plasma folate (P < 0.0001), cSHMT C1420T (P < 0.05) and glutathione (P < 0.001). To conclude, the aberrations in one-carbon metabolism induce oxidative stress in sporadic breast cancer either by affecting the folate pool or by impairing remethylation.