The aim of our study was to assess, from the perspective of the National Health Services in Spain, the cost-effectiveness of quantitative ultrasound (QUS) as a prescreen referral method for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry (DXA) in postmenopausal women of the general population. Using femoral neck DXA and heel QUS. We evaluated 267 consecutive postmenopausal women 65 years and older and attending primary care physician offices for any medical reason. Subjects were classified as osteoporotic or nonosteoporotic (normal or osteopenic) using the WHO definition for DXA. Effectiveness was assessed in terms of the sensitivity and specificity of the referral decisions based on the QUS measurement. Local costs were estimated from health services and actual resource used. Cost-effectiveness was evaluated in terms of the expected cost per true positive osteoporotic case detected. Baseline prevalence of osteoporosis evaluated by DXA was 55.8%. The sensitivity and specificity for the diagnosis of osteoporosis by QUS using the optimal cutoff thresholds for the estimated heel BMD T-score were 97% and 94%, respectively. The average cost per osteoporotic case detected based on DXA measurement alone was 23.85 euros. The average cost per osteoporotic case detected using QUS as a prescreen was 22.00 euros. The incremental cost-effectiveness of DXA versus QUS was 114.00 euros per true positive case detected. Our results suggest that screening for osteoporosis with QUS while applying strict cufoff values in postmenopausal women of the general population is not substantially more cost-effective than DXA alone for the diagnosis of osteoporosis. However, the screening strategy with QUS may be an option in those circumstances where the diagnosis of osteoporosis is deficient because of the difficulty in accessing DXA equipment.