Importance The rate of postoperative pancreatic fistula (POPF) after distal pancreatectomy ranges from 13% to 64%. To prevent POPF, polyglycolic acid (PGA) mesh was introduced, but its effect has been evaluated only in small numbers of patients and retrospective studies. Objective To evaluate the efficacy of PGA mesh in preventing POPF after distal pancreatectomy. Design, Setting, and Participants Prospective randomized clinical, single-blind (participant), parallel-group trial at 5 centers between November 2011 and April 2014. The pancreatic parenchyma was divided using a stapling device; no patient was given prophylactic octreotide. Perioperative and clinical outcomes were compared including POPF, which was graded according to the criteria of the International Study Group For Pancreatic Fistulas. A total of 97 patients aged 20 to 85 years with curable benign, premalignant, or malignant disease of the pancreatic body or tail were enrolled (44 in the PGA group and 53 in the control group). Interventions Patients in the PGA group underwent transection of the pancreas and application of fibrin glue followed by wrapping the PGA mesh around the remnant pancreatic stump. Main Outcomes and Measures The primary end point of this study was the development of a clinically relevant POPF (grade B or C by the International Study Group grading system). The secondary end point was the evaluation of risk factors for POPF. Results The study therefore evaluated a total of 97 patients, 44 in the PGA group and 53 in the control group. Thirty-nine patients were women and 58 patients were men. There were no differences in mean (SD) age (59.9 [12.0] years vs 54.5 [14.1] years,P = .05), male to female ratio (1.0:1.3 vs 1.0:1.7,P = .59), malignancy (40.9% vs 32.1%,P = .37), mean (SD) pancreatic duct diameter (1.92 [0.75] mm vs 1.94 [0.95] mm,P = .47), soft pancreatic texture (90.9% vs 83.0%,P = .17), and mean (SD) thickness of the transection margin (16.9 [5.4] mm vs 16.4 [4.9] mm,P = .63) between the PGA and control groups. The rate of clinically relevant POPF (grade B or C) was significantly lower in the PGA group than in the control group (11.4% vs 28.3%,P = .04). Conclusions and Relevance Wrapping of the cut surface of the pancreas with PGA mesh is associated with a significantly reduced rate of clinically relevant POPF. Trial Registration clinicaltrials.gov Identifier:NCT01550406.