Therapies that stimulate angiogenesis show promise in revascularization of transplanted or ischemic tissues. Viral macrophage inflammatory protein-II (vMIP-II) is encoded by human herpesvirus 8, and it can be both immunosuppressive and proangiogenic. However, little has been done to characterize the potential of vMIP-II-induced angiogenesis. We engineered a vMIP-II lentiviral gene vector, transduced both mature endothelial cells and progenitors, and transplanted these in Matrigel templates as an in vivo angiogenesis model. Our results show that vMIP-II promotes new, functional, branching, and segmented vessels associated with smooth muscle cells and connected with the host vasculature. Angiogenesis is enhanced through host cells as well as through transplanted vMIP-expressing endothelial cells. As a proof-of-concept for using vMIP-II in clinical applications, we showed that islets co-transplanted with endothelial cells expressing vMIP-II were revascularized and survived in Matrigel templates, whereas no islets survived under control conditions. vMIP-II up-regulates the expression of multiple proangiogenic factors that can have a synergistic effect. These include vascular endothelial growth factor (VEGF), kinase insert domain receptor, neuropilin 2, carcinoembryonic antigen-related cell adhesion molecule 1, interleukin-1alpha, fibronectin, and integrins alpha3, alpha4, and alpha5. These results provide the first demonstration that vMIP-II is proangiogenic in vivo and can deliver this function to endothelial progenitors as well as to mature endothelial cells through vector-mediated gene delivery.