A newly discovered PDGF isoform, PDGF‐CC, is expressed in actively angiogenic tissues such as placenta, some embryonic tissues, and tumors. We test the possibility that PDGF‐CC promotes angiogenesis in vivo. The core domain (mature form) of human PDGF‐CC is sufficiently potent to stimulate neovascularization in the mouse cornea. The corneal angiogenic response induced by PDGF‐CC is robust although the area of neovascularization is smaller than those of FGF‐2‐and VEGF‐stimulated angiogenesis. Similarly, PDGF‐BB and PDGF‐AB induce angiogenic responses virtually indistinguishable from PDGF‐CCstimulated vessels. In contrast, PDGF‐AA displays only a weak angiogenic response in the mouse cornea. Although there was no significant difference in incorporation of mural cells to the newly formed blood vessels induced by PDGF‐BB and ‐CC, the percentage of mural cell positive vessels induced by PDGF‐AA was greater than those induced by FGF‐2, PDGF‐BB, and PDGF‐CC. In the developing chick embryo, PDGF‐CC induced branch sprouts from established blood vessels. In PDGF receptor‐transfected endothelial cells, PDGF‐CC activated the PDGF receptor alpha subunit (PDGFR‐a). PDGF‐CC, but not PDGF‐AA, was able to activate PDGFR‐p receptor in endothelial cells that coexpress both α and β forms of receptors. Thus, the PDGF‐CC‐mediated angiogenic response is most likely transduced by PDGF‐aa and ‐ap receptors. These data demonstrate that the PDGF family is a complex and important group of proangiogenic factors.—Cao, R., Bråkenhielm, E., Li, X., Pietras, K., Widenfalk, J, Östman, A., Eriksson, U., Cao, Y. Angiogenesis stimulated by PDGF‐CC, a novel member in the PDGF family, involves activation of PDGFR‐aa and ‐ap receptors. FASEB J. 16, 1575–1583 (2002)