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We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI\u2010NETs. Interestingly the expression of its receptor neuropilin\u20102 (NRP\u20102) was still maintained. This study aimed at deciphering the potential role of NRP\u20102 as a contributor to SI\u2010NET progression. The role of NRP\u20102 in SI\u2010NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and <jats:italic>in vivo<\/jats:italic> models. Data obtained from human SI\u2010NET tissues showed that membranous NRP\u20102 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP\u20102 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP\u20102 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP\u20102 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP\u20102 as a potential therapeutic target for SI\u2010NETs, and will foster the development of innovative strategies targeting this receptor. \u00a9 2019 Pathological Society of Great Britain and Ireland. 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