Osteoporosis is frequently undiagnosed before fracture because of the lack of availability of instruments to quantitate bone mass. To evaluate the utility of quantitative ultrasound (QUS) of the calcaneus to diagnose osteoporosis, we determined bone mineral density (BMD) of the posterior-arterior spine, total hip, and femoral neck by dual-energy X-ray absorptiometry (DXA) and QUS in 312 women aged 50 years and older. A risk factor assessment (simple calculated osteoporosis risk estimation [SCORE]) also was quantitated in all women. Ninety-four of the 312 women were diagnosed as osteoporotic based on T scores ≤ −2.5 at the spine, total hip, and/or femoral neck. The sensitivity of the individual central sites for the diagnosis of osteoporosis was 49% at the spine (46 of 94 women), 32% at the total hip (30 of 94 women), and 81% at the femoral neck (76 of 94 women). At a QUS T score ≤ −1, the peripheral technique had a sensitivity of 62% and a specificity of 72%. Combining a QUS T score of ≤ −1 followed by a risk factor assessment of women with a QUS T score ≥ −0.99 using a cut point of 11 increased sensitivity to 81% (comparable with femoral neck DXA) but decreased specificity to 58%. If peripheral QUS measurements and risk factor assessment are the only tools employed before initiation of therapy, the benefits of increased ease of diagnosis will need to be balanced against potentially unnecessary treatment in some normal patients and lack of treatment in some osteoporotic patients.