The role of angiogenesis in lymphoproliferative diseases is not well established. We demonstrate here that human lymphoma cells secrete vascular endothelial growth factor (VEGF) and express VEGF receptor 1 (VEGFR-1) and VEGFR-2. Proliferation of non-Hodgkin lymphoma (NHL) cells under serum-free conditions was enhanced by the addition of VEGF and was blocked by VEGFR-1- and VEGFR-2-specific antibodies. To differentiate between VEGF-mediated autocrine and paracrine effects on lymphoma growth, NOD/SCID mice engrafted with human diffuse large B-cell lymphoma (DLBCL) were treated with species-specific antibodies against human VEGFR-1 (6.12), human VEGFR-2 (IMC-1C11), murine VEGFR-1 (MF-1), or murine VEGFR-2 (DC101). Treatment with 6.12 or DC101 (targeting tumor VEGFR-1 and host VEGFR-2) reduced established DLBCL xenograft growth, whereas treatment with IMC-1C11 or MF-1 (targeting tumor VEGFR-1 and host VEGFR-1) had no effect. Decreased tumor volumes after 6.12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization, respectively, supporting the presence of autocrine VEGFR-1- and paracrine VEGFR-2-mediated pathways in lymphomagenesis. Inhibition of paracrine VEGF interactions (DC101) in these models was equivalent to their inhibition with rituximab. Combining DC101 with therapeutic agents (rituximab, 6.12, methotrexate) consistently improved tumor responses over those of single-agent therapy. These data support the further clinical development of VEGFR-targeted approaches for the therapy of aggressive DLBCL.