To address the cardiovascular effects of dietary soy containing phytoestrogens, we measured blood pressure (BP), lipids, vascular function (systemic arterial compliance and pulse wave velocity), and endothelial function (flow-mediated vasodilation) in a randomized, double-blind trial. Two hundred thirteen healthy subjects (108 men and 105 postmenopausal women), 50-75 yr old, received either soy protein isolate (40 g soy protein, 118 mg isoflavones) or casein placebo for 3 months. There were 34 withdrawals (16%), with 179 subjects (96 men and 83 women) completing the protocol. After intervention in the soy group, compared with casein placebo, urinary phytoestrogens increased, accompanied by a significant fall in BP reflected by the BP model (P < 0.01) encompassing mean change (+/-SEM) in systolic (-7.5 +/- 1.2 vs. -3.6 +/- 1.1 mm Hg, P < 0.05), diastolic (-4.3 +/- 0.8 vs. -1.9 +/- 0.7 mm Hg, P < 0.05), and mean BP (-5.5 +/- 1 vs. -0.9 +/- 1 mm Hg, P < 0.008). In the lipid model, soy induced greater changes, compared with placebo (P < 0.001). On individual analysis, significant contributors included a reduction in the low- to high-density lipoprotein ratio (-0.33 +/- 0.1 vs. 0.04 +/- 0.1 mmol/L, P < 0.05) and triglycerides (-0.2 +/- 0.05 vs. -0.01 +/- 0.05 mol/L, P < 0.05) and an increase in Lp(a) lipoprotein (+/- 95% confidence interval) [42 (range, 17-67) vs. 4 (range, -22-31) mg/L, P < 0.05], whereas total, low-density lipoprotein, and high-density lipoprotein cholesterol improved in both groups; but no treatment effect was demonstrated. The arterial functional model demonstrated no difference between groups; although again, overall function improved in both groups. On individual analysis, peripheral PWV (reflecting peripheral vascular resistance) improved with soy (P < 0.01), whereas flow-mediated vasodilation (reflecting endothelial function) declined (in males only), compared with casein placebo (P < 0.02). No effect of treatment on the hypothalamic-pituitary-gonadal axis was noted in males or females. In normotensive men and postmenopausal women, soy improved BP and lipids but, overall, did not improve vascular function. Potential adverse effects were noted, with a decline in endothelial function (in males only) and an increase in Lp(a). Further research in hypertensive and hyperlipidemic populations is needed.