In the Southwest Oncology Group phase II study S0108, patients with relapsed, aggressive non-Hodgkin’s lymphoma were treated with single agent bevacizumab (Avastin), a recombinant monoclonal antibody directed against VEGF. Pretreatment tissue or bone marrow specimens were examined by immunohistochemistry (IHC) for expression of VEGF and its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). Circulating endothelial cells (CEC) and plasma levels of VEGF, VCAM, and bFGF were measured at baseline, week 8, and at disease progression. Currently, 45 patients have been enrolled in the study and 18 have had baseline lymphoma specimens submitted and adequate for analysis by IHC for expression of VEGF and its receptors. In 7 of 10 (70%) patients with diffuse large cell lymphoma, the tumors expressed VEGF and either or both VEGF receptors. There was 100% concordance between VEGF and receptor expression in these samples. In 7of 8 (88%) mantle cell specimens examined, VEGF expression was also observed. Expression of both VEGFR-1 and VEGFR-2 was observed in 6 (67%) of these specimens. While VEGF and VEGFR-1 expression was restricted to the malignant cells, VEGFR-2 was predominantly expressed on the endothelial cells in the lymphoma specimens, and in those cases where it was also expressed by the tumor cells it was typically at lower intensity. In 1 of 5 patients with serial lymphoma specimens, VEGF expression increased in the lymphoma cells during the course of bevacizumab therapy. There was a wide range in the plasma levels of VEGF, bFGF, VCAM, and CEC between patients. During the course of treatment, plasma VEGF levels decreased (p = 0.02), VCAM levels increased (p = 0.05), and bFGF and CEC levels remained relatively stable. CEC, VCAM, and bFGF levels did not correlate with VEGF expression in lymphoma samples but there was a trend for lymphomas with higher VEGF expression (+2 or higher) to have higher baseline plasma levels of VEGF (median VEGF level 471 pg/ml compared to 224 pg/ml). Accrual of samples continues and the results will be updated as the analyses are available. The high rate of concordance between VEGF and its receptors in diffuse large cell and mantle cell lymphomas suggests that an autocrine pathway may be involved in lymphoma pathogenesis and/or progression. In addition, these results provide a strong rationale for targeting the VEGF pathway in the treatment of these 2 histologic subtypes of aggressive non-Hodgkin’s lymphoma.