We evaluated sex differences in the prospective association between adiponectin with BMD, bone loss, and fractures. Adiponectin, an adipose-derived protein with insulin-sensitizing properties, is also expressed in bone-forming cells. Conflicting results and sex differences in the adiponectin-BMD association have been reported in cross-sectional studies. Serum adiponectin was measured in fasting blood samples obtained in 1984–1987 in 447 postmenopausal women (mean age: 76 yr) and 484 men (mean age: 75 yr). Four years later, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. In 1992–1996, axial BMD was remeasured in 261 women and 264 men. Multivariable analysis adjusted for age, weight, calcium intake, type 2 diabetes, alcohol intake, and exercise. Among women, adiponectin was inversely associated with BMD at the femoral neck (β = −0.002, p = 0.007), total hip (β = −0.002, p = 0.009), lumbar spine (β = −0.003, p = 0.008), and midshaft radius (β = −0.002, p = 0.01) after 4.4 yr and at the femoral neck and total hip 8.6 yr later. Among men, adiponectin was inversely associated with BMD at the femoral neck, (β = −0.002, p = 0.03), total hip (β = −0.004, p < 0.001), and midshaft radius (β = −0.003, p < 0.001) after 4.4 yr and at the hip 8.6 yr later. Adiponectin was not associated with 4-yr bone loss in either sex but was associated with vertebral fractures (adjusted OR: 1.13; 95% CI: 1.08–1.23; p = 0.009) among men only. Adiponectin was inversely associated with BMD; however, sex differences were observed by anatomical site and with regards to vertebral fractures.