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BACKGROUND This study sought to explore the clinical effects of vancomycin-loaded calcium phosphate cement (CPC) in the treatment of chronic osteomyelitis. METHODS Ninety-eight patients with chronic osteomyelitis, who were treated at our Department from December 1st, 2014 to December 1st, 2015, were randomly allocated into the research group or the control group. Each group comprised 49 patients. Patients in the research group (Group A) received a 1-stage treatment of vancomycin-loaded CPC after debridement, while those in the control group (Group B) received an irrigation and drainage device that administered irrigated antibiotics. The treatment effects, recurrence rates, and safety outcomes of the two groups were observed. RESULTS Patients in the two groups were followed up with for a period of 12 months. The control group without recurrence in one case. There was some systemic adverse postoperative effects and safety issues. The X-ray film showed that CPC filling is good and part of the degradation of osteogenesis. Some patients in the research group the CPC particles were absorbed, the bone defect area was healed, after One-year postoperatively. Further, the cure rate was high. CONCLUSIONS One-stage vancomycin-loaded CPC implantation osteomyelitis lesions fill the die cavity, enable patients to continue to fight infection, induce bone defect osteogenesis, reduce the recurrence of chronic osteomyelitis, and are an effective method for treating chronic osteomyelitis. TRIAL REGISTRATION Chinese Clinical Trial Registry website (ChiCTR2100044724).