Neuropilin-2 (NRP-2) is a receptor for the Vascular Endothelial Growth Factor (VEGF) and the Semaphorin (Sema) families, two unrelated ligand families involved in angiogenesis and neuronal guidance. NRP-2 binds specifically VEGF-A and VEGF-C, however the biological relevance of these interactions in human endothelial cells is poorly understood. In this study, we show that both VEGF-A and VEGF-C induce the interaction of NRP-2 with VEGFR-2. This interaction correlated with an enhancement of the VEGFR-2 phosphorylation threshold. Overexpression of NRP-2 in primary human endothelial cells promoted cell survival induced by VEGF-A and VEGF-C. In contrast, the Sema-3F, another ligand for NRP-2, was able to inhibit human endothelial cell survival and migration induced by VEGF-A and VEGF-C. Moreover, a siRNA targeting specifically NRP-2 is a potent inhibitor of human endothelial cell migration induced by VEGF-A and VEGF-C. Thus, our data indicate that NRP-2 acts as a co-receptor that enhances human endothelial cell biological responses induced by VEGF-A and VEGF-C.