Neonatal exposure to soy isoflavones at levels similar to that of infants fed soy protein formula resulted in higher bone mineral density (BMD), improved bone structure, and greater bone strength at young adulthood in female CD-1 mice (1,2). Our objective in this study was to determine whether these improvements in bone quantity and quality at 4 mo of age provide protection against the deterioration of bone tissue that occurs after a decline in endogenous sex steroid production. Male and female CD-1 mice (n = 8-18 pups per group per gender) were randomized to subcutaneous injections of corn oil [negative control (CON)], daidzein + genistein (DG; 7 mg x kg body weight(-1) x d(-1)), or diethylstilbestrol [(DES); positive control, 2 mg x kg body weight(-1) x d(-1)) from postnatal d 1 to 5. At 4 mo of age, mice were ovariectomized (females) or orchidectomized (males) and studied to 8 mo of age. Females treated with DG had higher (P < 0.05) femur and vertebral bone mineral content (BMC) and BMD compared with the CON group. Microstructural analysis revealed that improvements in BMD induced by DG and DES were coupled with greater trabecular thickness at the lumbar spine. Importantly, structural improvements resulted in bones that were more resistant to fracture, as the peak load of the femoral midpoint and lumbar vertebra 2 were higher (P < 0.05) with DG compared with CON. Effects in males were not significant. In conclusion, short-term neonatal exposure to isoflavones provides protection against the deterioration of bone tissue in females but not males after a decline of endogenous sex steroid production.