Background Few evidences are available on the prognostic role of mesopancreas excision(MPe) for ampullary cancers(ACs). Aim of this study was to compare the long-term outcomes between pancreaticoduodenectomy(PD) with(PD-MPe group) and without(sPD group) MP. Methods Thirty-seven sPDs were matched and compared to 37 PD-MPes for perioperative outcomes, recurrence rate, disease-free(DFS) and overall survival(OS). Results The PD-MPe technique related to a significantly higher number of harvested lymph nodes[16 (±6)] as compared to the sPD [10 (±5); p < 0.0001]. Tumor recurrence was more frequent in the sPD cohort[21 (56.8%) vs 12 (32.4%) in the PD-MPe population; p = 0.03]. Although not statistically different, PD-MPe was associated with a better DFS(40% vs 35.7% for sPD; p = 0.08) and OS(59.3% vs 39.1% for sPD; p = 0.07). At the multivariate analysis, a higher number of lymph nodes retrieved and a more extensive lymphovascular clearance reached with the MPe technique, together with lymph nodes metastases, were recognized as independent prognostic factors for a worse OS and DFS. Discussion The PD-MPe technique is associated with a better oncological radicality thanks to the higher number of retrieved lymph nodes and to the more appropriate tumor clearance. This reflects in a lower incidence of tumor relapse and in improved outcomes in terms of OS and DFS.