Background: No published studies have directly examined the effect of soy protein with isoflavones on bone or bone turnover in perimenopausal women. Objective: Our objective was to determine the effects of 24 wk of consumption of soy protein isolate with isoflavones (80.4 mg/d) in attenuating bone loss during the menopausal transition. Design: Perimenopausal subjects were randomly assigned, double blind, to treatment: isoflavone-rich soy (SPI+; n = 24), isoflavone-poor soy (SPI-; n = 24), or whey (control; n = 21) protein. At baseline and posttreatment, lumbar spine bone mineral density (BMD) and bone mineral content (BMC) were measured by using dual-energy X-ray absorptiometry. At baseline, midtreatment, and posttreatment, urinary N-telopeptides and serum bone-specific alkaline phosphatase (BAP) were measured. Results: The percentage change in lumbar spine BMD and BMC, respectively, did not differ from zero in the SPI+ or SPI- groups, but loss occurred in the control group (-1.28%, P = 0.0041; -1.73%, P = 0.0037). By regression analysis, SPI+ treatment had a positive effect on change in BMD (5.6%; P = 0.023) and BMC (10.1%; P = 0.0032). Baseline BMD and BMC (P less than or equal to 0.0001) negatively affected the percentage change in their respective models; baseline body weight (P = 0.0036) and bone-free lean weight (P = 0.016) contributed positively to percentage change in BMD and BMC, respectively. Serum BAP posttreatment was negatively related to percentage change in BMD (P = 0.0016) and BMC (P = 0.019). Contrast coding using analyses of covariance with BMD or BMC as the outcome showed that isoflavones, not soy protein, exerted the effect. Conclusion: Soy isoflavones attenuated bone loss from the lumbar spine in perimenopausal women.