ABSTRACT Lymphatic vascular development is regulated by vascular endothelial growth factor receptor‐3 (VEGFR‐3), which is activated by its ligands VEGF‐C and VEGF‐D. Neuropilin‐2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF‐C and VEGF‐D interact with NP2, VEGF‐C in a heparin‐independent and VEGF‐D in a heparin‐dependent manner. We also mapped the domains of VEGF‐C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR‐3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF‐C or VEGF‐D. NP2 also interacted with VEGFR‐3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.—Kärpänen, T., Heckman, C. A., Keskitalo, S., Jeltsch, M., Ollila, H., Neufeld, G., Tamagnone, L., Alitalo, K. Functional interaction of VEGF‐C and VEGF‐D with neuropilin receptors. FASEB J. 20, 1462–1472 (2006)