Background and Aims With the development and popularity of laparoscopic techniques, laparoscopic pancreatoduodenectomy (PD) has been gradually adopted in the clinical setting. However, because of the challenging surgical difficulty of LPD, its efficacy and safety have some degree of uncertainty. Therefore, this study was performed to further assess the short-term efficacy and safety of LPD through a retrospective analysis of the clinical data of patients undergoing LPD and those undergoing open pancreatoduodenectomy (OPD) during the same period.Methods The data of patients undergoing LPD and OPD in the Department of General Surgery, Tianjin Medical University General Hospital from February 2019 to September 2021 were collected. The main clinical variables were compared between the two groups of patients.Results A total of 160 patients meeting the eligibility criteria were included for analysis, with 25 cases in LPD group and 103 cases in OPD group. There were no significant differences in terms of age, body mass index (BMI), preoperative testing parameters between two groups (all P>0.05). The median operative time in LPD group was significantly longer than that in OPD group (450 min vs. 400 min，P=0.003), while other surgical variables that included blood transfusion rate, intraoperative blood loss, and lesion size showed no statistical difference between the two groups (all P>0.05). In addition, the BMI of the patients exerted no significant influences on the variables associated with the two procedures (all P>0.05). The median length of postoperative hospital stay was shortened (12 d vs. 27 d, P<0.001) and the incidence of postoperative delayed gastric emptying was reduced in LPD group compared with OPD group (5.6% vs. 33.7%,P=0.002), and there were no statistical differences with regard to the postoperative TNM stage, postoperative pathological results, and concentration of amylase in drainage fluid on postoperative day 3 as well as the incidence rates of other postoperative complications, repeated operation and patients' death between the two groups (all P>0.05). Comparison between patients undergoing portal vein resection and reconstruction in LPD group (8 cases) and OPD group (12 cases) showed that the operative time and length of hospitalization were significantly longer and the intraoperative blood loss was significantly higher in the former than those in the latter (all P<0.05).Conclusion LPD has the similar short-term efficacy and safety with OPD, and moreover, LPD is superior to OPD in terms of postoperative recovery and incidence of postoperative delayed gastric emptying. Nevertheless, LPD requires a prolonged operative time, especially combined with vascular reconstruction, resulting in increased intraoperative blood loss and lengthened postoperative hospital stay. Performing LPD requires high-level surgical skills of the surgeons, which provides great impetus for further development and standardization of this complex surgical procedure.