Background: We investigated the clinical effectiveness of antimicrobial prophylaxis in lower-extremity open fractures following the Eastern Association for the Surgery of Trauma Guidelines.Methods: This observational, retrospective, single-center study included adults with lower-extremity open fractures of the ankle, tibia, fibula, or femur. The primary endpoint was the incidence of osteomyelitis within 12 months of the fracture. Secondary endpoint comparisons were the time of antibiotic initiation and drug selection.Results: A total of 90 patients were included. Patients suffered from Gustilo and Anderson grades I (14%), II (54.7%), and III (31.3%) fractures. Almost all patients received cefazolin (98%). Among grade III fractures, 59.3% (16/27) of patients received additional gram-negative coverage as recommended by the guidelines. The osteomyelitis rate was 8.9%. There was no difference in osteomyelitis rates among patients with grade III fractures who received or did not receive additional gram-negative coverage: 18.8% (3/16) and 0 (0/11) (p=0.248), respectively. There was no correlation between median antibiotic start time or antibiotic stop time after closure and the development of osteomyelitis, respectively. Resistant organisms caused 50% (4/8) of the osteomyelitis cases. On univariate analysis, obesity had the most significant association with osteomyelitis (p=0.026).Conclusions: Bacterial resistance was common among cases of osteomyelitis in our cohort. Obesity was associated with a higher rate of osteomyelitis.