Despite many existing strategies used to reduce the rates of surgical site infection (SSI), these are still fairly frequent complications that pose a challenge for orthopedic surgeons. Therefore, the search for more effective methods of perioperative infection prophylaxis became a main subject of research, with the goal of decreasing postoperative morbidity, mortality, and costs. Thus, the present study sought to assess the effectiveness of intra-wound vancomycin powder in orthopedic surgery SSI prophylaxis.A systematic review and meta-analysis study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols 2015 (PRISMA-P 2015). A comprehensive literature search was performed to identify controlled studies on the rates of SSI with or without the local use of vancomycin powder. Exclusion and inclusion criteria were applied. A meta-analysis with random effects was performed.Out of 412 titles that met the criteria, 7 studies regarding spine surgery were included: 4 prospective and 3 retrospective studies. A total of 6,944 cases were identified, and they were divided into 2 groups: the control group (3,814 patients), to whom intrawound vancomycin was not administered, and the intervention group (3,130 patients), to who vancomycin was administered locally. We observed that 64 (2.04%) patients in the intervention group developed SSI, in contrast to 144 (3.75%) patients in the control group. The results of the meta-analysis showed that the local use of vancomycin powder had an statistically significant protective effect against SSI in cases of spine surgery, with a relative risk (RR) of 0.59 and a 95% confidence interval (95%CI) of 0.35–0.98.The use of prophylactic intrawound vancomycin powder has a protective effect against SSI in spine surgeries; however, further prospective trials are needed to endorse its use in orthopedic surgeries.