Background: Surgical site infections (SSIs), particularly periprosthetic joint infections (PJI), following a primary total joint arthroplasty (TJA) impose a major burden by increasing morbidity, mortality, disability rate, and health expenditure. Surgeons are increasingly using topical vancomycin powder as a preventative measure, but the effectiveness of this method has been debated in TJA. Thus, we designed a meta-analysis to compare the outcomes after primary TJA between a group treated with topical vancomycin powder and an untreated control group aiming to answer: 1) whether the application of topical vancomycin powder can reduce the infection rate after primary total joint replacement; 2) are the main types of pathogens causing SSIs after the application of topical vancomycin powder different from those of patients not using topical vancomycin? Materials and methods: A meta-analysis was conducted in accordance with the PRISMA guidelines. We included retrospective cohort studies and prospective randomized controlled trials of patients who underwent primary total joint arthroplasty with and without vancomycin powder application before wound closure and reported the SSI rates. The English literature in the PubMed (MEDLINE), EMBASE, Web of Science, and the Cochrane Library databases was comprehensively searched. Literature search, data extraction and quality assessment were conducted by 2 authors. The main outcomes were SSI and PJI rates, and the secondary outcome was the bacterial spectrum. Statistical analyses were performed with the Review Manager (RevMan) Version 5.3. Results: Six retrospective cohort studies and 3 prospective cohort studies with 4512 participants were included (2354 in vancomycin group and 2158 in the control group). In the TJA group, the vancomycin powder-treatment resulted in a significantly lower proportion of patients with SSIs (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.61 (p < 0.001)) or PJI (RR = 0.37, 95% CI = 0.23–0.60 (p < 0.001)). In the total hip arthroplasty group, the vancomycin powder treatment decreased the rate of SSIs and PJI by 66% (RR = 0.34, 95% CI = 0.15–0.78 (p = 0.01)) and 74% (RR = 0.26, 95% CI = 0.10–0.67 (p = 0.005)), respectively. In the total knee arthroplasty group, the vancomycin powder decreased the rate of SSIs and PJI by 67% (RR = 0.43, 95% CI = 0.26–0.70 (p < 0.001)) and 66% (RR = 0.44, 95% CI = 0.25–0.77 (p = 0.004)) respectively. Staphylococcus aureus (or methicillin-sensitive Staphylococcus aureus) (6 in vancomycin group versus 11 in control group) was the most common pathogenic bacteria, followed by Staphylococcus epidermidis (1 in vancomycin group versus 2 in control group) and methicillin-resistant Staphylococcus aureus (2 in vancomycin group versus 4 in control group). Pseudomonas aeruginosa was the main gram-negative pathogen, with 3 cases in the control group and 1 case in the vancomycin powder-treatment group. Discussion: The local application of vancomycin powder could significantly decrease the rate of SSIs and PJI in primary TJA without modifying the spectrum of bacteria involved. We recommend topical administration of the vancomycin powder before wound closure after a full evaluation of the patients. Level of evidence: III; meta-analysis. © 2020