We investigated the effects of soy isoflavone intake on breast cancer in a prospective study of 35,303 Singapore Chinese women enrolled during April 1993 to December 1998 in the Singapore Chinese Health Study. At recruitment, each subject was personally administered a validated semiquantitative food frequency questionnaire covering 165 food and beverage items. As of December 31,2005, 629 had developed breast cancer following an accumulation of 338,242 person-years. Using Cox regression and adjusting for age at interview, year of interview, dialect group, education, family history of breast cancer, age when periods became regular, parity, menopausal status, body mass index (BMI), n-3 fatty acid, and other covariates, we found breast cancer risk was reduced significantly in association with high soy intake. Relative to women with lower (below median) soy intake (<10.6 mg isoflavone per 1000 Kcal), women with higher (above median) intake showed a significant 18% risk reduction (relative risk (RR)=0.82, 95% confidence interval (CI)=0.70-0.97). This inverse association was apparent mainly in postmenopausal women (RR=0.74, 95% CI=0.61-0.90), and was not observed in premenopausal women (RR=1.04, 95% CI=0.77-1. 40). Among postmenopausal women, the soy-breast cancer association was stronger in those above median BMI (RR=0.67, 95% CI=0.51-0.88) than in leaner women (RR=0.83, 95% CI=0.62-1.11). Duration of follow-up modified the soy-breast cancer association, the effect being twice as large among women with 10+ vs fewer years of follow-up. Neither oestrogen nor progesterone receptor status of the tumours materially influenced the association. These prospective findings suggest that approximately 10 mg of isoflavones per day, obtained in a standard serving of tofu, may have lasting beneficial effects against breast cancer development.