Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle-aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow-up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were −1.14%/year, −1.17%/year, and −1.51%/year, respectively, in women, and −0.27%/year, −0.34%/year, and −0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose-response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations. © 2012 American Society for Bone and Mineral Research.