Periampullary carcinoma is a relatively rare malignant gastrointestinal tumor, encompassing malignancies of the Vater's ampulla, pancreatic head, distal common bile duct, and duodenal papilla. The anatomy of this area is intricate, with a narrow spatial structure and complex surrounding relationships. When it comes to treating tumors in this area, surgery is the preferred option. However, in clinical practice, there are often situations where certain patients are unable to undergo surgery or experience postoperative recurrence due to various reasons. Consequently, the use of adjuvant treatment, particularly chemotherapy, has become an essential approach in managing periampullary cancer. The lack of unified and clear recommendations in domestic and foreign clinical guidelines is attributed to the diverse sources of tissue in this region, the complexity of chemotherapy regimens, and the unclear efficacy of chemotherapy. Therefore, the role of chemotherapy in periampullary carcinoma still needs to be further explored and studied. Through a comprehensive review of domestic and foreign literature and an analysis of clinically relevant treatment experiences, we have identified an important finding: (1) through HE staining and immunohistochemistry, it can be classified into intestinal type originating from intestinal tissues, pancreatic biliary type originating from pancreatic or bile duct tissues, and mixed type originating from both intestinal, pancreatic or bile duct tissues; (2) The chemotherapy regimen should be selected based on the tumor's histopathological origin, as choosing an appropriate regimen can improve the survival time of patients with periampullary carcinoma; (3) selection of 5-FU based on chemotherapy regimens for patients with intestinal-type (IN-type), selection of gemcitabine based on chemotherapy regimens may be more beneficial for patients with pancreatic biliary-type (PB-type) and ambiguous-type (AM-type). However, the final conclusion needs to be clarified by more rigorous prospective randomized controlled trials. Through a systematic analysis of research in this field, we believe that the traditional understanding of periampullary carcinoma should be changed in clinical work: firstly, in clinical work, we should collectively call the tumour in this region as periampullary carcinoma, instead of traditionally calling it duodenal papillary cancer, which will affect our judgement of the patient's prognosis and the choice of chemotherapy regimen. Secondly, we should discard the traditional concept that the prognosis of patients with periampullary carcinoma is better than that of pancreatic cancer and bile duct cancer. At present, the prognosis of patients with the IN-type may be better than that of patients with the PB-type; however, the prognosis of patients with the PB-type is not much different from that of patients with pancreatic and bile duct cancers. Thirdly, we need to be aware of histopathological typing, and it is recommended that chemotherapy regimens should be selected based on histopathological typing; studies should also be based on histopathological typing in clinical studies, which can eliminate some of the confounding factors and lead to more accurate conclusion.