Osteoporotic fracture is considered to result from reduced bone strength and to be related to decreased bone mass and impaired bone architecture. Quantitative ultrasound measurements (QUS) of bone, that may reflect certain architectural aspects of bone, have been shown to be associated with fracture, but it is not clear whether the association is independent of bone mineral density (BMD). This study was designed to examine the contributions of cortical QUS and BMD measurements to the prediction of fracture risk in postmenopausal Caucasian women. Speed of sound (SOS) at the distal radius, tibia, and phalanx (Sunlight Omnisense) and BMD at the lumbar spine and femoral neck (GE Lunar) were measured in 549 women, aged 63.2 +/- 12.3 years (mean +/- SD; range, 49-88 years), including 77 fracture cases. Lower SOS at the distal radius, tibia, and phalanx, which were correlated with each other, were associated with increased risk of fracture. Independent predictors of fracture risk (in multivariate analysis) were distal radius SOS (OR per SD = 1.8; 95% CI, 1.3-2.4), femoral neck BMD (OR per SD = 1.9; 95% CI, 1.4-2.4), and age (OR per 5 years = 1.2; 95% CI, 1.0-1.5). Approximately 30% of the women had distal radius SOS T-scores <-2.5; however, only 6.6% of women had both BMD and SOS T-scores <-2.5. Among the 77 fracture cases, only 14 (18.2%) had both BMD and QUS T-scores below -2.5. These data in postmenopausal women suggest that speed of sound at the distal radius was associated with fracture risk, independent of BMD and age. The combination of QUS and BMD measurements may improve the accuracy of identification of women who will sustain a fracture.