BACKGROUND: Despite guideline recommendations, routine application of topical antibiotic agents to sternal edges after cardiac surgery is seldom done. Recent randomized controlled trials have also questioned the effectiveness of topical vancomycin in sternal wound infection prophylaxis. METHODS: We screened multiple databases for observational studies and randomized controlled trials assessing the effectiveness of topical vancomycin. Random effects meta-analysis and risk-profile regression were performed, and randomized controlled trials and observational studies were analyzed separately. The primary endpoint was sternal wound infection; other wound complications were also analyzed. Risk ratios served as primary statistics. RESULTS: Twenty studies (N = 40,871) were included, of which 7 were randomized controlled trials (N = 2,187). The risk of sternal wound infection was significantly reduced by almost 70% in the topical vancomycin group (risk ratios [95% confidence intervals]: 0.31 (0.23-0.43); P < .00001) and was comparable between randomized controlled trials (0.37 [0.21-0.64]; P < .0001) and observational studies (0.30 [0.20-0.45]; P < .00001; Psubgroup = .57). Topical vancomycin significantly reduced the risk of superficial sternal wound infections (0.29 [0.15-0.53]; P < .00001) and deep sternal wound infections (0.29 [0.19-0.44]; P < .00001). A reduction in the risk of mediastinitis and sternal dehiscence risks was also demonstrated. Risk profile meta-regression showed a significant relationship between a higher risk of sternal wound infection and a higher benefit accrued with topical vancomycin (ß-coeff. = -0.00837; P < .0001). The number needed to treat was 58.2. A significant benefit was observed in patients with diabetes mellitus (risk ratios 0.21 [0.11-0.39]; P < .00001). There was no evidence of vancomycin or methicillin resistance; on the contrary, the risk of gram-negative cultures was reduced by over 60% (risk ratios 0.38 [0.22-0.66]; P = .0006). CONCLUSION: Topical vancomycin effectively reduces the risk of sternal wound infection in cardiac surgery patients.