BACKGROUND: Recent studies support early drain removal after pancreaticoduodenectomy in patients with a drain fluid amylase on postoperative day 1 (DFA1) level of ≤5,000. The use of DFA1 to guide drain management is increasingly common among pancreatic surgeons; however, the benefit of checking additional drain fluid amylases beyond DFA1 is less known. We sought to determine whether a change in drain fluid amylase (ΔDFA) is a more reliable predictor of clinically relevant postoperative fistula than DFA1 alone. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Plan, pancreaticoduodenectomy patients with intraoperative drain placement, known DFA1, highest recorded drain fluid amylase value on postoperative day 2 to 5 (DFA2nd), day of drain removal, and clinically relevant postoperative fistula status were reviewed. Logistic models compared the predictive performance of DFA1 alone versus DFA1 + ΔDFA. RESULTS: A total of 2,417 patients with an overall clinically relevant postoperative fistula rate of 12.6% were analyzed. On multivariable regression, clinical predictors for clinically relevant postoperative fistula included body mass index, steroid use, operative time, and gland texture. These variables were used to develop model 1 (DFA1 alone) and model 2 (DFA1 + ΔDFA). Model 2 outperformed model 1 in predicting the risk of clinically relevant postoperative fistula. According to model 2 predictions, the risk of clinically relevant postoperative fistula increased with any rise in drain fluid amylase, regardless of whether the DFA1 was above or below 5,000 U/L. The risk of clinically relevant postoperative fistula significantly decreased with any drop in drain fluid amylase, with an odds reduction of approximately 50% corresponding with a 70% decrease in drain fluid amylase (P < .001). A risk calculator was developed using DFA1 and a secondary DFA value in conjunction with other clinical predictors for clinically relevant postoperative fistula. CONCLUSION: Clinically relevant postoperative fistula after pancreaticoduodenectomy is more accurately predicted by DFA1 and ΔDFA versus DFA1 in isolation. We developed a novel risk calculator to provide an individualized approach to drain management after pancreaticoduodenectomy.