BACKGROUND: The high morbidity and mortality rates of pancreaticoduodenectomy are mainly associated with pancreaticojejunal anastomosis, the most fragile and susceptible to complications such as clinically relevant postoperative pancreatic fistula. AIMS: The alternative fistula risk score and the first postoperative day drain fluid amylase are predictors of the occurrence of clinically relevant postoperative pancreatic fistula. No consensus has been reached on which of the scores is a better predictor; moreover, their combined predictive power remains unclear. To the best of our knowledge, this association had not yet been studied. METHODS: This study assessed the predictive effect of alternative fistula risk score and/or drain fluid amylase on clinically relevant postoperative pancreatic fistula in a retrospective cohort of 58 patients following pancreaticoduodenectomy. The Shapiro-Wilk and Mann-Whitney tests were applied for assessing the distribution of the samples and for comparing the medians, respectively. The receiver operating characteristics curve and the confusion matrix were used to analyze the predictive models. RESULTS: The alternative fistula risk score values were not statistically different between patients in the clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 59.5, p=0.12). The drain fluid amylase values were statistically different between clinically relevant postoperative pancreatic fistula and non- clinically relevant postoperative pancreatic fistula groups (Mann-Whitney U test 27, p=0.004). The alternative fistula risk score and drain fluid amylase were independently less predictive for clinically relevant postoperative pancreatic fistula, compared to combined alternative fistula risk score + drain fluid amylase. CONCLUSION: The combined model involving alternative fistula risk score >20% + drain fluid amylase=5,000 U/L was the most effective predictor of clinically relevant postoperative pancreatic fistula occurrence following pancreaticoduodenectomy.