MULTIMERIN2 (MMRN2), also known as Endoglyx-1, is an extracellular matrix glycoprotein whose function has so far remained elusive. Given its specific localization in tight association with the endothelium we hypothesized that this protein could modulate neo-angiogenesis. By multiple assays we showed that MMRN2 significantly impaired endothelial cell (EC) migration and organization of a functional vessel network. The interaction of ECs with MMRN2 induced a striking impairment of VEGFR1 and VEGFR2 activation. We focused our attention on VEGFR2, a chief regulator of angiogenesis, and clarified that MMRN2 interfered with the VEGF/VEGFR2 axis through a direct binding with VEGF-A. This novel interaction was assessed in several assays and the affinity was estimated (Kd∼ 50 n M). We next questioned whether the anti-angiogenic properties of MMRN2 could impair tumor growth. Although overexpression of MMRN2 by HT1080 cells did not affect their growth and apoptotic rate in vitro, it remarkably affected their growth in vivo. In fact, MMRN2-positive cells failed to efficiently grow and form well-vascularized tumors; a similar outcome was observed following treatment of established tumors with a MMRN2 adenoviral construct. Tumor-section immunostaining revealed a strong co-localization of VEGF-A with the ectopically expressed MMRN2. These novel findings suggest that VEGF may be sequestered by MMRN2 and be less available for the engagement to the receptors. Taken together these results highlight MMRN2 as a crucial player in the regulation of EC function, neo-angiogenesis and hence tumor growth. We hypothesize that secreted and deposited MMRN2 may function as a homeostatic barrier halting the sprouting of novel vessels, and suggest that these studies may embody the potential for the development of novel tools for cancer treatment.