INTRODUCTION: The purpose of this present study is to investigate the efficacy of vancomycin-loaded VK100 silicone cement drug delivery system in the treatment of implant-related methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in rats. MATERIALS AND METHODS: Thirty-six adult (18-20 weeks old) female Sprague-Dawley rats were included in the study. All rats underwent experimental osteomyelitis surgery via injecting 100 µL bacterial suspension of MRSA into the medullary canal. After a 2-week duration for the formation of osteomyelitis model, rats were assigned randomly into four groups: control (C), systemic vancomycin (V), local vancomycin-loaded VK100 silicone cement (vVK100), and systemic vancomycin and local vancomycin-loaded VK100 silicone cement (V+vVK100). The following treatment protocols were administered to each group for 4 weeks. For group C, 0.9% saline solution equivalent to the volume of vancomycin dose (approximately 1 ml/kg) was administered intraperitoneally twice daily (12-h intervals). For group V, 15 mg/kg of vancomycin was administered intraperitoneally twice daily (12-h intervals). For group vVK100, vVK100 polymer was included so that the intramedullary canal of the rats are affected. For group V+vVK100, vVK100 polymer was included so that the intramedullary canal of the rats are affected and 15 mg/kg of vancomycin was administered intraperitoneally twice daily (12-h intervals). After 4 weeks of treatment, clinical, radiologic, microbiologic, and histopathologic evaluations were performed for all groups. RESULTS: Results of this study revealed that all scores of the evaluation criteria for the treatment groups (groups V, vVK100, and V+vVK100) decreased due to the treatment protocols when compared to group C. These results show the effectiveness of all treatment protocols for the implant-related chronic MRSA osteomyelitis. However, there were no statistical difference between these three protocols. CONCLUSIONS: vVK100 polymer, as a local antibiotic delivery system, seems to be an effective method for the treatment of implant-related chronic MRSA osteomyelitis.