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Postoperative pancreatic fistula (PF) remains one of the most significant complications after pancreaticoduodenectomy (PD). Recently, studies have suggested that post-PD serum hyperamylasemia (HA) may be a risk factor. In this study, we evaluate the relationship of pancreas texture and post-operative serum amylase levels in determining PF risk. This retrospective cohort study evaluated all patients who underwent PD at Thomas Jefferson University from 2009 to 2014. The highest postoperative serum amylase level from postoperative day (POD) 0 to POD 5 was obtained. Chi-square analyses and odds ratio (OR) evaluated the relationship between pancreas texture, serum amylase level, and the development of PF. Data from 524 consecutive patients were analyzed. Serum amylase threshold value of 165 IU/L yielded greatest accuracy from the receiver operating characteristic curve analysis (Sensitivity, 0.70; specificity, 0.72). Grade B or C PF were more common among HA patients (20 vs 3%; P < 0.001). HA was associated with increased rates of PD-associated complications. On multivariable analysis, early postoperative serum HA was more predictive of PF risk (OR, 4.87; P < 0.001) than either pancreatic duct size ≤3 mm (OR, 2.97; P = 0.01) or pancreas texture (OR,1.87; P = 0.05)., Conclusion: The presence of HA on POD 0 or POD 1 is more predictive than soft pancreas texture or small pancreas duct size alone.