Background and aims. The natural history, clinical characteristics and optimal management of duodenal neuroendocrine neoplasms (dNENs) are unclear. Present multicenter study was aimed at analyzing the natural history of patients with dNENs. The secondary goal was to evaluate the overall (OS) and progression-free survival (PFS), according to the histological features, stage at initial diagnosis, and other possible prognostic parameters. Methods. This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. Results. From 2000 to 2017, 108 patients were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox?s multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. Conclusions. dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.