Pancreatic lipomatosis is characterized as massive lipid infiltration of the pancreatic tissue. Although its etiology is ill defined; obesity, diabetes mellitus, chronic pancreatitis, hereditary pancreatitis, and conditions that cause pancreatic ductal obstruction, for example tumors and stones, are related to its pathogenesis. Recently, with the increased use of computerized tomography and magnetic resonance imaging, it has become possible to observe the fat replacement of the pancreas. Herein, we report a 60-year-old man complaining of abdominal pain and weight loss. Preoperative work-up revealed a locally advanced (Stage III) pancreatic adenocarcinoma. Multimodal treatment was carried out and a 100% complete response was detected after neoadjuvant therapy. The patient underwent a standard pancreaticoduodenectomy, without complications. The tissue pathology revealed lipomatosis of the pancreas. He was disease-free and symptom-free at 1 year follow-up. To our knowledge, this is the first report in the literature of pancreatic head carcinoma with total fat replacement of the pancreas after neoadjuvant chemoradiotherapy.