PURPOSE: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of tyrosine kinases receptors (TKR) in humans, implicated in cell proliferation, adhesion, migration, tumor angiogenesis, invasion and metastasis. The aim of the present study is to assess the expression of EPHs in neuroendocrine neoplasms (NENs). METHODS: Immunohistochemical staining of specimens of 30 patients with gastroenteropancreatic and lung NENs was performed for EPH-A1, EPH-A2, EPH-A4, EPH-A5 protein expression, in addition to ki-67 multiplication index and programmed death-ligand 1. Additionally, we performed a systematic review of the available literature in three different databases reporting on the expression of EPH in all neuroendocrine neoplasms. RESULTS: Positive expression was seen in 16/19 (84%) specimens for EPH-A1, 15/23 (65%) for EPH-A2, 21/24 (88%) for EPH-A4, 24/26 (92%) for EPH-A5. EPH-A1 was expressed in 9/9 pancreatic, 3/4 small intestine, but not in one lung NEN, EPH-A2 in 5/10 pancreatic, 3/4 small intestine and lung, and in one of each of gastric, appendix, colorectal, and cervical NENs, respectively. EPH-A4 showed positive expression in 9/11 pancreatic, 4/4 small intestine, 3/3 lung specimens and EPH-A5 in 10/11, 4/4 and 4/4, respectively. Data retrieved from the systematic review of the literature in combination with the data from the present study are suggestive of a frequent EPH expression in pituitary, thyroid, lung and gastroenteropancreatic NENs, yet, with varying expressions of the single receptor subtypes. CONCLUSION: EPHs may have a role in NEN tumorigenesis, prognosis as well as a role in the evolving molecular-targeted therapies.