Sushi repeat-containing protein X-linked 2 (SRPX2) is a newly identified chondroitin sulfate proteoglycan that is markedly elevated in multiple solid tumors. It is also suggested that SRPX2 is associated with angiogenesis. A conditioned medium of SRPX2 overexpressing colorectal cancer (CRC) cells and SRPX2 recombinant protein was used to evaluate the effect of secretory SRPX2 on the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) and the involved molecular mechanisms. It was revealed that the activity of SRPX2 is dependent on the urokinase-type plasminogen activator receptor and cooperation of the integrin αvβ3 co-receptor. Subsequent studies showed that both PI3K/Akt and Ras/MAPK pathways and phosphorylation of focal adhesion kinase is involved in the intracellular signaling pathway of SRPX2/uPAR. This study suggests that SRPX2 promotes angiogenesis of HUVECs through the cooperation of the uPAR and integrin/FAK pathway.