Background Chromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. Methods In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA 1-439 ) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. Results Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA 1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25 th -75 th -percentiles); total-CgA: 1.85 nM (1.01–4.28) vs 0.75 nM (0.52–0.89), p = 0.004; VS-1: 2.76 nM (1.09–7.10) vs 0.29 nM (0.26–0.32), p <0.001, respectively], but not of CgA 1-439 or CgA 1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p <0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1. Conclusion These findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA. © 2018 Corsello et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.