Consuming soy and soy isoflavones has been shown to cause modest improvements in plasma lipids, lipoproteins, and indices of insulin sensitivity in postmenopausal women. The effect of soy on such end points is attributed often to estrogen receptor agonism by isoflavones. Recent in vitro studies suggest that isoflavones, in combination with high estrogen concentrations (within the range seen circulating in premenopausal women), function as estrogen receptor antagonists that potentially may counteract the beneficial effects seen with soy consumption. We studied insulin sensitivity in 15 premenopausal nonhuman primates consuming either a high isoflavone soy diet or a soy-free casein/lactalbumin diet for 4 months. Insulin sensitivity was measured by intravenous glucose tolerance testing, hyperinsulinemic-euglycemic clamps, and insulin-stimulated insulin receptor and protein kinase B phosphorylation levels in muscle. In addition, plasma lipids, adiponectin, thyroid hormone, and body weights are reported. We show that high isoflavones do not adversely affect insulin sensitivity but do significantly alter insulin secretion to glucose stimulation. Small but significant increases in thyroxine and increased high-density lipoprotein cholesterol were observed as has been reported commonly with soy intake. These study results demonstrate that consumption of soy containing high isoflavone levels is not associated with changes in insulin sensitivity in the high estrogen milieu of the premenopausal female.