We explored the antitumor efficacy of a strategy using recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a xenogeneic protein vaccine, which we have demonstrated to have effective antiangiogenic activities in several tumor models, in combination with low-dose adriamycin in lymphoma model. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomly divided into four groups: combination therapy (xVEGF plus adriamycin), xVEGF treatment alone, adriamycin treatment alone, and normal saline (NS) groups, and received relevant treatments. Tumor growth, survival rate of tumor-bearing mice, and potential toxicity of regimens above were investigated. Anti-VEGF antibodies and anti-VEGF antibody-producing B cells (APBCs) were detected by Western blot analysis and enzyme-linked immunospot (ELISPOT) assay, respectively. In addition, microvessel density (MVD) within tumor tissues and tumor cell apoptosis were determined by immunohistochemistry and TUNEL staining, respectively. Our data showed that combination therapy inhibited tumor growth and improved survival of tumor-bearing mice significantly, and complete regression of tumor was observed in 3 of 10 mice in combination group in EL4 lymphoma model.Survival rate of mice was significantly higher in combination group than that in xVEGF alone group,in adriamycin alone group (P<0.05),or that in NS group (P<0.01). Remarkably, the combination treatment resulted in not only significant antiangiogenic effects but also promotion of tumor cell apoptosis. The calculated indexes of combination therapy showed synergistic relationship in terms of inhibition of tumor growth, antiangiogenesis, induction of tumor cell apoptosis. In addition, anti-VEGF antibodies and APBCs were found in mice treated with either xVEGF vaccine alone or combination treatment. No marked toxicities were found in the treated mice. In summary, these findings may provide an effective combination approach for lymphoma therapy in the future.