Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arte‐riogenic factors. Using in vivo angiogenesis and isch‐emic hind‐limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF‐2) in combinations with PDGF‐AA and PDGF‐AB, two members of the platelet‐derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF‐AA/FGF‐2 and PDGF‐AB/FGF‐2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF‐2 up‐regulates PDGFR‐α and ‐β expression levels in the newly formed blood vessels. Interestingly, PDGF‐AB/ FGF‐2, but not PDGF‐AA/FGF‐2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti‐PDGFR‐β neutralizing antibody significantly blocks PDGF‐AB/FGF‐2‐induced vessel stability. These findings demonstrate that PDGFR‐β receptor is essen‐tial for vascular stability. Similarly, PDGF‐AB/FGF‐2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF‐AB/FGF‐2 leads to dramatic im‐provement of the paw's skin perfusion. Immunohisto‐chemical analysis of the treated skeletal muscles con‐firms that a combination of PDGF‐AB and FGF‐2 significantly induces arteriogenesis in the ischemic tis‐sue. A combination of PDGF‐AB and FGF‐2 would be optimal proangiogenic agents for the treatment of ischemic diseases.—Zhang, J., Cao, R., Zhang, Y., Jia, T., Cao, Y., Wahlberg, E. Differential roles of PDGFR‐α and PDGFR‐β in angiogenesis and vessel stability. FASEB J. 23, 153‐163 (2009)