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Minimally invasive pancreaticoduodenectomy (MIPD) remains one of the most challenging abdominal procedures. Safety and feasibility remain controversial when comparing MIPD with open pancreaticoduodenectomy (OPD). The aim of this systematic review and meta-analysis was to evaluate the feasibility and safety of MIPD versus OPD.A systematic review of the literature was performed to identify studies comparing MIPD and OPD. Postoperative complications, intraoperative outcomes and oncologic data, and postoperative recovery were compared.There were 27 studies that matched the selection criteria. Totally 1306 cases of MIPD and 5603 cases of OPD were included. MIPD was associated with a reduction in postoperative hemorrhage (odds ratio [OR] 1.60; 95% confidence interval [CI] 1.03–2.49; P = .04) and wound infection (OR 0.44, 95% CI 0.30–0.66, P < .0001). MIPD was also associated with less estimated blood loss (mean difference [MD] −300.14 mL, 95% CI −400.11 to −200.17 mL, P < .00001), a lower transfusion rate (OR 0.46, 95% CI 0.35–0.61; P < .00001) and a shorter length of hospital stay (MD −2.95 d, 95% CI −3.91 to −2.00 d, P < .00001) than OPD. Meanwhile, the MIPD group had a higher R0 resection rate (OR 1.45, 95% CI 1.18–1.78, P = .0003) and more lymph nodes harvested (MD 1.34, 95% CI 0.14–2.53, P = .03). However, the minimally invasive approach proved to have much longer operative time (MD 71.00 minutes; 95% CI 27.01–115.00 minutes; P = .002) than OPD. Finally, there were no significant differences between the 2 procedures in postoperative pancreatic fistula (P = .30), delayed gastric emptying (P = .07), bile leakage (P = .98), mortality (P = .88), tumor size (P = .15), vascular resection (P = .68), or reoperation rate (P = .11).Our results suggest that MIPD is currently safe, feasible, and worthwhile. Future large-volume, well-designed randomized controlled trials (RCT) with extensive follow-up are awaited to further clarify this role.