Vascular endothelial growth factor₁₆₅ (VEGF₁₆₅) and semaphorin3A (SEMA3A) elicit pro- and antiangiogenic signals respectively in endothelial cells (ECs) by binding to their receptors VEGFR-2, neuropilin-1 (NRP1), and plexin-A1. Here we show that the VEGF₁₆₅-driven angiogenic potential of multiple myeloma (MM) ECs is significantly higher than that of monoclonal gammopathy of undetermined significance (MGUS) ECs (MGECs) and human umbilical vein (HUV) ECs. This is probably due to a constitutive imbalance of endogenous VEGF₁₆₅/SEMA3A ratio, which leans on VEGF₁₆₅ in MMECs but on SEMA3A in MGECs and HUVECs. Exogenous VEGF₁₆₅ induces SEMA3A expression in MGECs and HUVECs, but not in MMECs. Moreover, by counteracting VEGF₁₆₅ activity as efficiently as an anti-VEGFR-2 antibody, exogenous SEMA3A restrains the over-angiogenic potential of MMECs. Our data indicate that loss of endothelial SEMA3A in favor of VEGF₁₆₅ could be responsible for the angiogenic switch from MGUS to MM.