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Background Prevention of surgical site infection (SSI) is a public health challenge. Our objective was to determine if prophylactic negative-pressure wound therapy (pNPWT) allows preventing SSI after laparotomy. Methods Medline, Embase, and Web of Science were searched on 6 October 2019 for original studies reporting the incidences of SSI in patients undergoing open abdominal surgery with and without pNPWT. Risk differences (RDs) between control and pNPWT patients and risk ratios (RRs) for SSI were obtained using random-effects models. Results Twenty-one studies (2930 patients, 5 randomized controlled trials [RCTs], 16 observational studies) were retained for the analysis. Pooled RD between patients with and without pNPWT was −12% (95% confidence interval [CI], −17% to −8%; I 2 = 57%; P  < .00001) in favor of pNPWT. That risk difference was −12% (95% CI, −22% to −1%; I 2 = 69%; P  = .03) when pooling only RCTs (792 patients). pNPWT was protective against the incidence of SSI with a RR of 0.53 (95% CI,.40–.71; I 2 = 56%; P  < .0001). The effect on pNPWT was more pronounced in studies with an incidence of SSI ≥20% in the control arm. The preventive effect of pNPWT on SSI remained after correction for potential publication bias. However, when pooling only high-quality observational studies (642 patients) or RCTs (527 patients), significance was lost. Conclusions Existing studies suggest that pNPWT on closed wounds is protective against the occurrence of SSI in abdominal surgery, but these findings need to be confirmed by more high-quality evidence, preferentially in subgroups of patients with an incidence of SSI ≥20% in the control arm. [ABSTRACT FROM AUTHOR]