We report a case of locally advanced pancreatic tail adenosquamous carcinoma that was treated by performing R0 resection after neoadjuvant chemotherapy with S-1 and gemcitabine. A 75-year-old man visited our hospital because of left lateral abdominal pain. On the basis of computed tomography and endoscopic biopsy findings, an 80-mm locally advanced pancreatic tail carcinoma with direct invasion to the gastric upper body, splenic flexure of the colon, and left kidney was diagnosed. Combined chemotherapy with S-1 and gemcitabine was initiated for reduction in the tumor size. After 11 courses of treatment, computed tomography revealed a partial response in tumor size reduction. Grade 3 neutropenia was observed as an adverse event. Distal pancreatectomy, proximal gastrectomy, partial resection of the descending colon, resection of the left kidney and left adrenal gland, and D2 lymph node dissection were performed. The pathological diagnosis was adenosquamous carcinoma in the pancreatic tail, and an R0 resection was achieved. However, a month after surgery, multiple distant liver metastases were observed. Neoadjuvant chemotherapy with S-1 and gemcitabine may reduce the tumor size in locally advanced pancreatic tail adenosquamous carcinoma and increase the R0 resection rate. However, treatment for distant metastasis is warranted in cases of pancreatic adenosquamous carcinoma.