Background: Mesenteric approach is infracolic artery-first approach during pancreatoduodenectomy (PD) with complete circumferential lymphadenectomy around the superior mesenteric artery (SMA). In this study, we evaluated clinical and oncological benefits of this procedure for pancreatic ductal adenocarcinoma (PDAC) of the pancreas head. Methods: Between 2000 and 2015, 237 consecutive PDAC patients underwent PD. Among them, 72 experienced mesenteric approach (mesenteric group) and 165 conventional approach (conventional group). A matched-pairs group consisted of 116 patients (58 patients in each group) matched for age, sex, resectability status, and neoadjuvant therapy. Surgical and oncological outcomes were compared between the two groups. Results: Intraoperative blood loss was lower in mesenteric group than in conventional group in both resectable PDAC (R-PDAC) and borderline resectable PDAC (BR-PDAC) on matched-pairs analyses (R-PDAC, 312.5 vs. 501.5 ml, P=0.023, BR-PDAC, 507.5 vs. 920 ml, P=0.003). The negative surgical margins (R0) and the overall survival (OS) rates in mesenteric group were better in R-PPDAC patients (R0 rates, 100 vs. 87%, P=0.045, OS, P=0.021), although there were no significant differences in BR-PDAC patients. Conclusion: Mesenteric approach might reduce blood loss by early ligation of the vessels to the pancreatic head. Furthermore, it might increase R0 rate, leading to improvement of survival for R-PDAC patients. However, R0 and survival rates could not be improved only by mesenteric approach for BR-PDAC patients. Therefore, effective multidisciplinary treatment is essential to improve survival in BR-PDAC patients. To confirm theses results, we are conducting a randomized, controlled multicenter trial comparing the oncological and surgical outcomes between the mesenteric and conventional approaches during PD for patients with PDAC (MAPLE-PD trial). Three-hundred sixty-one patients have been enrolled in this study. We are going to report the results of MAPLE-PD trial in August 2023 after we will have observed the last patient for 2 years.