: Postoperative pancreatic fistula and post-hepatectomy liver failure remain significant complications after HPB surgery; however, superficial surgical site infection (SSI) is the most frequent wound-related complication. Closed-incision negative-pressure wound therapy (ciNPWT) has been proposed to reduce superficial contamination, yet no liver-focused quantitative synthesis exists. We aimed to evaluate the effectiveness and safety of prophylactic ciNPWT after hepatopancreatobiliary (HPB) surgery. : MEDLINE, Embase, and PubMed were searched from inception to 30 April 2025. Randomized and comparative observational studies that compared ciNPWT with conventional dressings after elective liver transplantation, hepatectomy, pancreatoduodenectomy, and liver resections were eligible. Two reviewers independently screened, extracted data, and assessed risk of bias (RoB-2/ROBINS-I). A random-effects Mantel-Haenszel model generated pooled risk ratios (RRs) for superficial SSI; secondary outcomes were reported descriptively. : Twelve studies (seven RCTs, five cohorts) encompassing 15,212 patients (3561 ciNPWT; 11,651 control) met the inclusion criteria. Device application lasted three to seven days in all trials. The pooled analysis demonstrated a 29% relative reduction in superficial SSI with ciNPWT (RR 0.71, 95% CI 0.63-0.79; < 0.001) with negligible heterogeneity (I 0%). Absolute risk reduction ranged from 0% to 13%, correlating positively with the baseline control-group SSI rate. Deep/organ-space SSI (RR 0.93, 95% CI 0.79-1.09) and 90-day mortality (RR 0.94, 95% CI 0.69-1.28) were unaffected. Seven studies documented a 1- to 3-day shorter median length of stay; only two reached statistical significance. Device-related adverse events were rare (one seroma, no skin necrosis). : Prophylactic ciNPWT safely reduces superficial SSI after high-risk HPB surgery, with the greatest absolute benefit when baseline SSI risk exceeds ≈10%. Its influence on deep infection and mortality is negligible.