Background: Use of laparoscopic pancreaticoduodenectomy (LPD) in place of open pancreaticoduodenectomy (OPD) remains controversial. Our aim was to evaluate the results of LPD versus OPD in non-pancreatic periampullary adenocarcinoma (NPPC), a less aggressive tumor. Methods: Here, 488 NPPC patients who underwent LPD or OPD were analyzed in this study. The propensity score matching was used to balance the patients in two groups. Statistical analysis was conducted to investigate the differences between LPD and OPD in patients with NPPC. Results: The LPD group had shorter operative time, less intraoperative bleeding, and less postoperative hospital stay than OPD group. The 30- and 90-day mortality rates were significantly lower in LPD than in OPD group. There was no statistical difference in long-term survival between the two groups. Conclusions: For NPPC, LPD may be the preferred surgical treatment due to its advantages over OPD in terms of intraoperative blood loss and short-term mortality. (C) 2020 The Authors. Published by Elsevier Inc.