OBJECTIVES Treatment with LIPUS results in greater increases in bone density and greater reductions in bone gap area as compared to sham control in tibia fractures with NU(no progression of healing for at least four months). Fractures that do not heal after several months represent significant clinical and economic burden to health care systems. Five to ten percent of all fractures are eventually classified as nonunions[NU], fractures that fail to heal or will not heal without intervention. Interventions include treatment by cast/brace, surgery, electrical stimulation, or low-intensity pulsed ultrasound[LIPUS]. METHODS Two primary effectiveness variables, change of bone density and gap area during treatment, were selected as surrogates for bone healing. Abbreviated treatment period was maximum that sham treatment could be administered ethically. Both variables measured by blinded central reviewers from CT-scans taken before/after termination of treatment. All adverse events recorded, evaluated. Treatment duration was 16 weeks. Patients instructed to apply device once daily for 20 minutes. Control (sham) devices were visually identical but did not transmit ultrasound waves. Neither patients nor physicians could recognize shams. RESULTS A total of 101 patients enrolled (51 LIPUS, 50 sham), mean age 42.6 (active) versus 45.1 years (sham). Based on log-transformed data, mean improvement in bone density was 1.34 (90% CI 1.14 to 1.57) times greater for patients randomized to LIPUS compared to sham (p=0.002). A mean reduction in bone gap area also favored LIPUS treatment (p=0.014). CONCLUSIONS Double-blind, intent-to-treat analyses demonstrated statistically significant superior effectiveness for LIPUS device compared to sham in terms of both endpoints over 16 weeks of treatment. Estimated increase in bone density among patients randomized to LIPUS treatment was 34% greater than among patients randomized to sham. A significantly greater mean reduction in bone gap area after LIPUS treatment was also shown. Evaluation of adverse events showed that ultrasound therapy is safe.