Generalized edema can occasionally be found in the terminal stage of cancer, but it can also result from exocrine pancreatic insufficiency in patients with pancreatic cancer. We encountered a case of generalized edema in a patient with recurrent pancreatic cancer after pancreatoduodenectomy, which improved with pancreatic enzyme replacement therapy. A 71-year-old man underwent pancreatoduodenectomy for pancreatic head cancer at a previous hospital in 2014. Two years after surgery, he was diagnosed as having recurrence by computed tomography and was initiated on chemotherapy; however, as the anemia and generalized edema worsened, the patient was referred to our hospital for palliative therapy in 2018. At the time of admission, the patient had severe generalized edema and difficulty in walking. Because the patient gave no history of receiving oral treatment with digestive enzyme preparations, we suspected that exocrine pancreatic insufficiency could be the cause of the edema. The patient was initiated on pancreatic enzyme replacement therapy, and three months later, marked resolution of the edema was observed and the patient became ambulant. Administration of digestive enzyme preparations for exocrine pancreatic insufficiency is essential after pancreatic resection. Caution is required as overlooking prompt replacement may result in chronic worsening. Even in exocrine pancreatic insufficiency associated with pancreatic cancer, the QOL rapidly improves with pancreatic enzyme replacement.