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Objectives: Patients who have undergone pancreaticoduodenectomy (PD) may experience a long-term decrease in quality of life because of postoperative pancreatic dysfunction (such as digestive and absorption disorders) and fatty liver as a result of combined resection of the duodenum, gallbladder, and bile duct. The present study investigated the usefulness of pancrelipase for the prevention of pancreatic dysfunction after PD. Methods: The data from 73 patients who underwent PD in a single institution were analyzed. Patients who underwent PD during 2007–2011 were administered the low-titer pancreatic enzyme preparations berizym® and pancreatin® (first period group), while patients who underwent PD during 2012–2017 were administered the high-titer pancreatic enzyme preparation pancrelipase (second period group). The following measures of the nutrition status were examined before and after PD: serum albumin concentration, total lymphocyte count, serum total cholesterol concentration, body mass index, controlling nutrition status (CONUT) index, Onodera’s prognostic nutrition index (PNI), and liver computed tomography values. Results: The second period group had significantly higher serum albumin concentrations at 3 and 6 months postoperatively, serum total cholesterol concentrations at 1 month postoperatively, and Onodera’s PNI values at 3 and 6 months postoperatively than the first period group. The CONUT index values at 6 months after PD were significantly lower in the second period group than in the first period group. Conclusions: Pancrelipase is useful in improving the nutrition status and preventing fatty liver after PD.