Osteoporosis is one of the major complications of glucocorticoid (GC) therapy. Few data are available on the usefulness of quantitative ultrasound (QUS), a technique that could also theoretically provide information on bone structure, in the management of glucocorticoid-induced osteoporosis (GIO). This study aimed (1) to evaluate the ability of QUS in detecting bone impairment and in being associated with the prevalence of fragility fracture in GC patients; and (2) to assess whether QUS parameters, and particularly the graphic trace analysis of QUS signal at phalanges, show any peculiar pattern of GIO. We studied 192 patients (136 women and 56 men, mean age 56.7 +/- 14.2 years) on treatment with GCs for at least 6 months, and 192 sex- and age-matched controls. In all subjects, we measured bone mineral density (BMD) at lumbar spine and at femur by DXA, and ultrasound parameters at calcaneus and phalanges. All DXA and QUS parameters were significantly lower in GC patients than in controls and in fracture than in nonfracture GC patients. BMD at lumbar spine showed the best ability in discriminating GC patients with or without fractures. Among QUS parameters, stiffness showed a discriminatory ability significantly better than AD-SoS. BMD at lumbar spine and total femur, stiffness, and AD-SoS are able to predict the odds of fragility fracture event. QUS parameters of the postmenopausal GC patients (n = 105) and of the postmenopausal healthy controls (n = 101) were also compared with those obtained in a separate sample of 90 postmenopausal osteoporotic women (PMO). All parameters were significantly lower in GC patients and in PMO than in controls, without any significant difference between GC and PMO. Our findings show that QUS can be useful in the assessment of glucocorticoid-induced bone impairment. In addition, in this study we found no alteration in QUS parameters or in the graphic trace analysis which could differentiate between GIO and PMO. Further longitudinal studies are needed to define the role of QUS in the prediction of fracture risk and in the clinical management of GIO.