Objective: To explore the risk factors of prosthetic infection around the prosthesis after the treatment of osteosarcoma. Methods: A retrospective analysis of 223 patients with osteosarcoma treated with tumor prosthesis in our hospital from August 2015 to August 2020 was performed. According to the postoperative infection, the infected patients were included in the observation group, and the uninfected patients were included in the control group. The baseline data, perioperative indicators and prognosis of the two groups were collected for comparative analysis. The related risk factors that lead to postoperative infection around the prosthesis are summarized, and its impact on the survival and prognosis of patients is examined. Results: Among the 223 patients with osteosarcoma who underwent prosthesis treatment, 25 cases of prosthetic infection occurred after surgery, the incidence rate was 11.21%, of which 10 cases of synovial fluid showed positive bacterial culture, and 8 cases showed positive intraoperative freezing. Low levels of neutrophils and white blood cells before operation, longer operation time, and postoperative radiotherapy are all high-risk factors leading to infection around the prosthesis (P<0.05). Among the dead patients, those with infection around the prosthesis had a longer survival time (P<0.05). Conclusion: For patients with osteosarcoma undergoing prosthetic treatment, low levels of neutrophils and white blood cells before surgery, longer operation time, and postoperative radiotherapy are all high-risk factors leading to infection around the prosthesis, and a variety of clinical measures need to be taken to prevent infection.