© 2014, The Society for Surgery of the Alimentary Tract. Introduction: Improvements in the ability to predict pancreatic fistula could enhance patient outcomes. Previous studies demonstrate that drain fluid amylase on postoperative day 1 (DFA1) is predictive of pancreatic fistula. We sought to assess the accuracy of DFA1 and to identify a reliable DFA1 threshold under which pancreatic fistula is ruled out.Methods: Patients undergoing pancreatic resection from November 1, 2011 to December 31, 2012 were selected from the American College of Surgeons-National Surgical Quality Improvement Program Pancreatectomy Demonstration Project database. Pancreatic fistula was defined as drainage of amylase-rich fluid with drain continuation >7 days, percutaneous drainage, or reoperation for a pancreatic fluid collection. Univariate and multi-variable regression models were utilized to identify factors predictive of pancreatic fistula.Results: DFA1 was recorded in 536 of 2,805 patients who underwent pancreatic resection, including pancreaticoduodenectomy (n = 380), distal pancreatectomy (n = 140), and enucleation (n = 16). Pancreatic fistula occurred in 92/536 (17.2 %) patients. DFA1, increased body mass index, small pancreatic duct size, and soft texture were associated with fistula (p < 0.05). A DFA1 cutoff value of <90 U/L demonstrated the highest negative predictive value of 98.2 %. Receiver operating characteristic (ROC) curve confirmed the predictive relationship of DFA1 and pancreatic fistula.Conclusion: Low DFA1 predicts the absence of a pancreatic fistula. In patients with DFA1 < 90 U/L, early drain removal is advisable.