OBJECTIVE Results of recent clinical trials indicate that mammalian estrogens may be less effective in reducing coronary heart disease risk than once thought. This study was designed to determine whether mammalian estrogen's coronary artery dilator benefits could be enhanced by adding soy with phytoestrogens. DESIGN Forty-five atherosclerotic, ovariectomized monkeys were fed one of four diets: (1) atherogenic diet with casein/lactalbumin as source of protein (Casein, n = 12); (2) casein diet with micronized estradiol equivalent to a woman's dose of 1 mg/day (Casein + E2, n = 12); (3) atherogenic diet with soy protein with phytoestrogens (129 mg woman/day equivalent) (Soy, n = 11); and (4) the soy diet plus estradiol (Soy + E2, n = 10). METHODS Quantitative angiography and intravascular Doppler were done after 6 months of experimental diet to measure changes in diameter and coronary flow reserve in the circumflex coronary artery in response to intracoronary acetylcholine and nitroglycerin. RESULTS Arteries from the E2 and Soy + E2 groups dilated in response to acetylcholine 5 +/- 3% and 12 +/- 5%, respectively (p < 0.05 vs. Casein). There was an interactive effect of soy and E2 on dilator response to acetylcholine (p < 0.05). Flow reserve was greatest in animals fed casein + E2 and soy + E2 (2.3 +/- 0.3 and 2.6 +/- 0.5, respectively; p < 0.05 vs. Casein). Soy protein alone had no effect on coronary artery reactivity (p > 0.05). CONCLUSION Soy protein itself does not affect coronary artery dilator responses but interacts with estradiol to promote dilator responses to acetylcholine.