Screening of osteoporosis by quantitative ultrasound (QUS) has become widely available in Europe, but no clear strategies for its clinical use have been established. The aim of this study was to validate the use of QUS in a cross-sectional study carried out in three primary care centers. Measurements of calcaneal QUS and bone mineral density (BMD) at proximal femur were obtained by dual-energy X-ray absorptiometry (DXA). Osteoporosis was diagnosed by DXA T-score ≤ -2.5 at the femoral neck. Sensitivity, specificity, kappa index, and receives operator characteristics (ROC) curve QUS values were calculated with respect to the standard reference. Both positive and negative likelihood ratios (LR) were used to calculate the optimum cut-off levels. Two hundred and sixty-seven women aged 65 or older were included. Fifty-five percent had osteoporotic femoral neck BMD values (T-score ≤ -2.5). The same threshold for QUS yielded a lower prevalence of osteoporosis (10%). Women with BMD diagnosis of osteoporosis were older and showed lower age-adjusted values for all QUS parameters (p < 0.001). Area under the curve (AUC) ranged from 0.662-0.678 for the different QUS parameters; correlation and concordance of all parameters with femoral neck BMD were statistically significant (p < 0.001). Cut-off values calculated from the AUC yielded 61.1% sensitivity and 65.3% specificity for the best QUS parameter (i.e., Estimated Heel T-score ≤ -1.55). Estimated Heel T-score values of +0.05 or above ruled out osteoporosis (LR 0.18), whereas those -2.50 or below supported the diagnosis (LR 5.98). The application of these cutoff points allowed classification of 22.1% of cases. In conclusion, in postmenopausal women, QUS screening conclusively confirms or rules out osteoporosis in approximately one-fifth of cases, thereby avoiding the need for a DXA measurement.