Several studies have compared laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in patients with periampullary carcinoma; however, only a few studies have made such a comparison on patients with ampulla of Vater cancer (AVC). We compared the perioperative and oncologic outcomes between LPD and OPD in patients with AVC using propensity-score-matched analysis. A total of 359 patients underwent PD due to AVC during the study period (76 LPD, 283 OPD). After propensity score matching, the LPD group showed significantly longer operation time than did the OPD group (400.2 vs. 344.6 min, p < 0.001). Nevertheless, the LPD group had fewer painkiller administrations (8.3 vs. 11.1, p < 0.049), fewer Grade II or more severe postoperative complications (15.9% vs. 34.8%, p = 0.012), and shorter postoperative hospital stays (13.7 vs. 17.3 days, p = 0.048), compared with the OPD group. There was no significant difference in recurrence-free outcomes and overall survival between the two groups (p = 0.754 and 0.768, respectively). Compared with OPD, LPD for AVC had comparative oncologic outcomes with less pain, less postoperative morbidity, and shorter hospital stays. LPD may serve as a promising alternative to OPD in patients with AVC.