Background: Postoperative pancreatic fistula is the leading cause of morbidity after distal pancreatectomy. Strategies investigated to reduce the incidence have been disappointing. Recent data showed a reduction in postoperative pancreatic fistula with the use of synthetic mesh reinforcement of the staple line. Methods: An RCT was conducted between May 2014 and February 2016 at four tertiary referral centres in Sweden. Patients scheduled for distal pancreatectomy were eligible. Enrolled patients were randomized during surgery to stapler transection with biological reinforcement or standard stapler transection. Patients were blinded to the allocation. The primary endpoint was the development of any postoperative pancreatic fistula. Secondary endpoints included morbidity, mortality, and duration of hospital stay. Results: Some 107 patients were randomized and 106 included in an intention-to-treat analysis (56 in reinforced stapling group, 50 in standard stapling group). No difference was demonstrated in terms of clinically relevant fistulas (grade B and C): 6 of 56 (11 per cent) with reinforced stapling versus 8 of 50 (16 per cent) with standard stapling (P = 0.332). There was no difference between groups in overall postoperative complications: 45 (80 per cent) and 39 (78 per cent) in reinforced and standard stapling groups respectively (P = 0.765). Duration of hospital stay was comparable: median 8 (range 2-35) and 9 (2-114) days respectively (P = 0.541). Conclusion: Biodegradable stapler reinforcement at the transection line of the pancreas did not reduce postoperative pancreatic fistula compared with regular stapler transection in distal pancreatectomy.