Optimal antibiotic management of patients with osteomyelitis remains a challenge for many clinicians. Although image-guided bone biopsy (IGB) remains the gold standard, its role in confirming diagnosis and guiding antibiotic management is not clear in patients with non-vertebral osteomyelitis.To determine the diagnostic yield of IGB and its impact on antibiotic management in non-vertebral osteomyelitis.Retrospective cohort study.Urban academic medical center.Patients admitted for non-vertebral osteomyelitis who underwent image-guided bone biopsy.Primary outcomes were microbiologic and histopathological results. We evaluated the impact of IGB on clinician-initiated changes in antibiotic regimen before and after biopsy.We evaluated 203 bone biopsies in 185 patients with clinical suspicion of osteomyelitis. 79% of patient received antibiotics prior to biopsy. Bone cultures were positive in 28% and histopathology confirmed osteomyelitis in 29%, but concordance was poor. Furthermore, clinical suspicion of infection was much higher, given that 68% received empiric antibiotics. Leukocytosis was significantly associated with positive cultures in multivariate analysis. There was no statistically significant correlation between antibiotic management and bone culture results. When culture yielded an organism, empiric regimens were kept the same, broadened or narrowed with equal frequency; targeted regimens were chosen only in 4 cases. Despite negative cultures in 98/138 cases having received empiric treatment, antibiotics were discontinued in only 8 cases. Even when empiric treatment was not given, negative cultures did not dissuade clinicians from eventual antibiotic use in a significant number of cases (17/48). In 46/71 patients whose final regimen included vancomycin, there was no evidence of current or past infection with MRSA.In patients with non-vertebral osteomyelitis, the diagnostic yield of image-guided bone biopsy is low, and clinicians frequently make decisions regarding antibiotic management that are not aligned with culture results.