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Background: Because of the established path of bacterial entry and contamination-associated mechanisms, grade 3 open orthopedic fractures represent a substantial infection risk. The Eastern Association for the Surgery of Trauma (EAST) guidelines recommended covering Staphylococcus aureus and adding aminoglycoside gram-negative coverage. Local institutional guidelines rely on ceftriaxone for gram negative coverage and add methicillin-resistant Staphylococcus aureus coverage with vancomycin. Patients and Methods: The electronic health records of adults admitted for a grade 3 open fracture between January 1, 2016, and October 31, 2021, were retrospectively reviewed. Patients who received cefazolin and gentamicin (CZ+GM) or ceftriaxone and vancomycin (CRO+VA) as prophylaxis were included. We recorded the rate of a composite treatment failure outcome of receipt of antibiotic agents, infection-related hospitalization, or subsequent debridement for injury-site skin and soft tissue infection or osteomyelitis. The presence of acute kidney injury (AKI) was also evaluated. Results: There were 65 patients included in the CZ+GM group and 53 patients in the CRO+VA group. Patients in the CZ+GM group were younger (mean 42.6 compared with 50.6 years; p = 0.02). Otherwise, there were no significant differences between groups' demographics, mechanism and site of injury, timeline of care, or surgical interventions. More patients in the CZ+GM arm met the composite treatment failure outcome, but it was not statistically significant (45% vs. 32%; p = 0.2). There were similar rates of treatment failure at 30 days (21% vs. 26%; p = 0.5) and for only osteomyelitis (8% vs. 9%; p = 1). Conclusions: The trend in numerically lower treatment failure rates in the CRO+VA group across outcomes provides sufficient evidence to continue the current local recommendations. Given our sample size, type 2 error may have occurred, and studies with greater power should analyze this question. [ABSTRACT FROM AUTHOR]