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Background: The treatment of open fractures of the tibial shaft is often complicated by delayed union and non-union. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention. Methods: In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively. Results: Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fe