OBJECTIVES: We undertook a study to evaluate relationships among blood phytoestrogen levels, lipoprotein levels, estrogen levels, and angiographically defined coronary artery disease in women. BACKGROUND: Evidence for a beneficial role and the potential mechanism(s) of plant estrogens (phytoestrogens) on blood lipoproteins in humans is controversial. METHODS: We evaluated 483 women enrolled in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation with coronary risk factors undergoing coronary angiography for evaluation for suspected ischemia for blood phytoestrogen levels (daidzein and genistein), lipoprotein levels [total cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-C)], estrogen levels (estradiol, bioavailable estradiol, estrone), and angiographic coronary artery disease using core laboratories. RESULTS: Higher blood levels of the phytoestrogen daidzein were associated with lower triglycerides (P = 0.01), higher HDL-C (P = 0.05) levels, and a beneficial total cholesterol to HDL-C ratio (P = 0.02). This beneficial association was evident among the subgroup of women with low [<184 pmol/liter (<50 pg/ml)] blood estradiol levels, regardless of age and lipoprotein levels. The phytoestrogen associations with lipoproteins were incrementally related to the magnitude of daidzein level and independent of other lipoprotein modulators. There were no detectable relationships between the phytoestrogen levels and angiographic coronary artery disease. CONCLUSIONS: Higher blood phytoestrogen daidzein levels are associated with beneficial lipoprotein levels in women with low estrogen levels, possibly by an estrogen receptor mechanism. These results suggest a potential explanation for the variable lipoprotein results observed in prior randomized controlled trials and call for investigation regarding subgroups of subjects who may preferentially benefit from dietary intake of food products, such as soy.