Equol binds to the estrogen receptor with greater affinity than its precursor, daidzein, an isoflavone found in soybeans. Inter-individual differences in the ability to produce equol may lead to differential effects of isoflavone intervention on human health. Here, we review previously published work from our laboratory on equol producer status and bone health in humans and in a mouse model of osteoporosis. We performed a 1-y, double-blind, randomized trial to compare the effects of isoflavone (75 mg of isoflavone conjugates/d; equivalent to 47 mg/d of the aglycone form) with those of placebo on bone mineral density (BMD), fat mass, and serum isoflavone concentrations in 54 early postmenopausal Japanese women classified by their equol-producer phenotype. Isoflavone intervention increased the serum equol concentration in equol producers but not in nonproducers (P < 0.04). The annualized changes in BMD in the total hip and intertrochanteric regions in the isoflavone-treated equol producers (-0.46 and -0.04%, respectively) were less than in the nonproducers (-2.28 and -2.61%, respectively). The annualized change in fat mass was lower in the equol producers compared with the nonproducers in the isoflavone group. The annualized changes in BMD and fat mass did not differ between the equol producers and nonproducers in the placebo group. Equol also inhibited bone loss and fat accumulation in estrogen-deficient osteoporotic mice. Our data suggest that prevention of bone loss and fat accumulation in early postmenopausal women by isoflavones may depend on an individual's equol-producing capacity.