Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has shown antitumor activity by inhibiting tumor angiogenesis in preclinical and clinical studies. However, bevacizumab monotherapy does not induce complete tumor regression. Therefore, additional treatments must be combined with bevacizumab to promote tumor regression. We previously showed that melanoma differentiation associated gene-7 (mda-7) protein exerts potent antitumor and antiangiogenic activity. Thus, in this study, we investigated the therapeutic effects of mda-7 in combination with bevacizumab using lung cancer as a model. In vitro, treatment of human umbilical vein endothelial cells with conditioned medium from Ad-mda7 plus bevacizumab-treated lung tumor cells showed reduced VEGF ligand-receptor binding, and decreased cell survival, resulting in growth arrest and apoptosis. In vivo, treatment of subcutaneous lung tumor xenografts with bevacizumab plus Ad-mda7 resulted in significant tumor growth inhibition and improved survival compared to tumor growth in control mice. Furthermore, tumors in all the Ad-mda7 plus bevacizumab-treated mice completely regressed, and these were tumor free through the study's end. Molecular analysis showed enhanced tumor cell apoptosis and reduced VEGF and CD31 expression in Ad-mda7 plus bevacizumab-treated tumors. Thus, Ad-mda7 and bevacizumab treatment produces a synergistic and complete therapeutic effect against human lung cancer.