Antiangiogenic immunotherapy, which targets molecules critical to tumor angiogenesis, is expected to counteract the negative effect of tumor cell genetic instability on the outcome of immunotherapy targeting tumor antigens. Previously, targeting of individual angiogenic molecules has been shown to inhibit tumor angiogenesis and limit tumor growth. Nevertheless, this approach may be bypassed by redundant angiogenic pathways. To overcome this limitation, we have developed an immunization strategy targeting multiple molecules critical to angiogenesis. To this end, hybrids of dendritic cells (DC) and syngeneic endothelial cells (EC) were used as immunogens, because (a) whole EC express multiple molecules involved in angiogenesis and (b) DC tumor cell hybrids are effective in generating self-antigen-specific immune responses. The immunization strategy included the administration of an agonist 4-1BB-specific monoclonal antibody (mAb), because it augments self-antigen-specific immune responses elicited by DC hybrids. Immunization of mice with DC-EC hybrids and 4-1BB-specific mAb inhibited the growth of B16.F10 melanoma and MC38 colon adenocarcinoma tumors. This effect is mediated by EC-specific CD4+ and CD8+ T-cell responses, which markedly inhibited tumor angiogenesis. No therapy-related side effects, except minor and transient hematologic changes, were observed. Our findings represent a useful background for the design of antiangiogenic immunotherapeutic strategies to control tumor growth in a clinical setting.