Despite that angiopoietin-2 (Ang2) produces more versatile and dynamic functions than angiopoietin-1 (Ang1) in angiogenesis and inflammation, the molecular mechanism that underlies this difference is still unknown. To define the role of oligomerization of Ang2 in activation of its receptor, Tie2, we designed and generated different oligomeric forms of Ang2 by replacement of the amino-terminal domains of Ang2 with dimeric, tetrameric, and pentameric short coiled-coil domains derived from GCN4, matrillin-1, and COMP. COMP-Ang2 strongly binds and activates Tie2, whereas GCN4-Ang2 and MAT-Ang2 weakly to moderately bind and activate Tie2. Although native Ang2 strongly binds to Tie2, it does not activate Tie2. Accordingly, COMP-Ang2 strongly promotes endothelial cell survival, migration, and tube formation in a Tie2-dependent manner, and the potency of COMP-Ang2 is almost identical to that of COMP-Ang1. Furthermore, the potency of COMP-Ang2-induced enhanced angiogenesis in the wound healing region is almost identical to the potency of COMP-Ang1-induced enhanced angiogenesis. Overall, there is no obvious difference between COMP-Ang2 and COMP-Ang1 in in vitro and in vivo angiogenesis. Our results provide compelling evidence that proper oligomerization of Ang2 is a critical determinant of its binding and activation of Tie2.