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Background: Antibiotic agents have been shown to improve outcomes in open extremity fractures. The first-generation cephalosporins, which are used most often, are often under-dosed based on weight and recommended frequency. Ceftriaxone offers a broader coverage and a decreased frequency of administration. Our institution began utilizing ceftriaxone for open fracture management in 2017 to address those concerns. Objective: To examine the efficacy of cefazolin versus ceftriaxone for open fracture management of extremity trauma. Patients and Methods: Retrospective study from 2015-2019 of patients who sustained open extremity fractures. Patients were stratified by antibiotic administered and Gustilo-Anderson grade. Outcomes included non-union/malunion, superficial surgical site infection (SSI), deep SSI, osteomyelitis, re-operation after index hospital visit, re-admission due to prior injury, limb loss, and death. Subgroup analysis stratified each antibiotic group by Gustilo-Anderson grade 1 or 2 and grade 3. Results: Data was collected from 2015 to 2019. Of the 1,149 patients, 619 patients met inclusion criteria. Three hundred fifty-five patients received cefazolin and 264 patients received ceftriaxone. There were no statistically significant differences between groups on specified outcomes. No statistically significant differences existed during subgroup analysis for the specified outcomes. Multivariable analysis demonstrated increased Gustilo-Anderson grade increased risk of infectious outcome. Conclusions: Ceftriaxone is a safe and effective alternative for open fracture extremity management that offers the advantage of 24-hour dosing and single antibiotic coverage for grade 3 open fractures. It does not increase infectious complications and offers benefits of resource efficiency.