Objectives: Open fractures with bone loss are common, disabling injuries. Biodegradable, load-bearing scaffolds able to carry high concentrations of local antibiotics are an emerging technology to address these injuries. This study investigates the use of such scaffolds with gentamicin (along with bone morphogenetic protein) in an infected rat open fracture model to decrease osteomyelitis and promote fracture healing. Methods: A contaminated open fracture was created in 32 Brown Norway rats. A comminuted femoral fracture was created, followed by crushing, and the 5-mm bone defect was inoculated with Staphylococcus aureus (10 colony-forming units/mL) and Escherichia coli (10 colony-forming units/mL). The scaffold was stabilized in the defect with an intramedullary Kirschner wire. Gentamicin was loaded onto the scaffolds at two doses, either 10 mg (n = 12) or 20 mg (n = 10). Controls (n = 10) received no antibiotics. All three groups had 10 μg bone morphogenetic protein loaded on the scaffold. Serial radiographs were obtained. Microbiologic analysis, microcomputed tomography, and histology were performed. Results: There was a statistically significant difference in the radiographic evidence of osteomyelitis (P = 0.004) and callus formation (P = 0.021) between the treated and control groups. Bone culture analysis results were not significant for S. aureus (P = 0.29) or E. coli (P = 0.25). There was no difference in the mean scaffold volume or density of the three treatment groups. Conclusions: Our results suggest that gentamicin applied to a biodegradable scaffold is effective at decreasing radiographically defined osteomyelitis in an infected open fracture. © 2010 by Lippincott Williams & Wilkins.