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New antibiotics have been developed targeting resistant microorganisms; however, limited information is available on their use in implant-related chronic osteomyelitis. We evaluated the infection control rate of linezolid in treating these challenging infections and delineate indications for its use. We retrospectively reviewed 22 consecutive adult patients with chronic implant-related osteomyelitis, treated with linezolid in addition to surgical débridement and implant removal. Osteomyelitis was associated with fracture fixation implants (n = 18) or arthroplasty implants (n = 4). Methicillin-resistant Staphylococcus aureus (MRSA) was the most common pathogen (10 of 22 patients). Fourteen patients had one or more comorbidity, including intravenous drug abuse in four patients. Indications for linezolid use included preference for oral administration in 13 patients, presence of vancomycin-resistant enterococcus (VRE) in five patients, and development of allergic reactions to vancomycin in four patients. Fourteen patients were followed for a minimum of 6 months (mean, 22 months; range, 6-34 months) with no recurrence of infection. Linezolid is a reasonable alternative for treating chronic implant-related osteomyelitis. Our treatment protocol, including linezolid, achieved control of infection in all patients despite the challenging nature of these infections due to patient comorbidities and resistant organisms.Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.