BACKGROUND Several small-scale studies have shown that wrapping polyethylene glycolic acid (PGA) mesh around the anastomotic site reinforced pancreaticojejunostomy following pancreatoduodenectomy (PD) with favorable outcomes. This study investigated the efficacy of PGA mesh for reducing postoperative pancreatic fistula (POPF) and evaluated other risk factors for POPF. METHODS This study enrolled 464 consecutive patients who underwent PD performed by one surgeon between 2006 and 2015, including a PGA group of 281 patients (60.6%) and a control group of 183 patients (39.4%). All pancreatico-enteric anastomoses were performed using double-layered, duct-to-mucosa, end-to-side pancreaticojejunostomy. RESULTS Mean patient age was 63.1 years. The rates of overall (27.0% vs. 37.2%, P = 0.024) and clinically relevant (Grades B, C; 13.9% vs. 24.0%, P = 0.006) POPF were significantly lower in the PGA than in the control group. Following propensity score matching, the rates of clinically relevant POPF (12.6% vs. 22.4%, P = 0.024) and complications (40.2% vs. 63.8%, P < 0.001) remained significantly lower in the PGA group. Multivariate analysis showed that non-pancreatic disease, greater blood loss, higher body mass index, and non-application of PGA mesh were significantly associated with the development of clinically relevant POPF. CONCLUSIONS PGA mesh reinforcement of pancreaticojejunostomy may prevent POPF as well as reducing overall abdominal complications after PD.