Intimal hyperplasia of vascular smooth muscle cells (VSMC) at the venous anastomosis of arteriovenous grafts represents the most common cause of vascular access failure in hemodialysis patients. Upstream release of growth factors from leukocytes activated by adhesion to the graft material may play a role in this lesion. We evaluated the effect of interaction of peripheral blood mononuclear cells (PBMC) with polytetrafluoroethylene (PTFE) on proliferation of VSMC. Vascular smooth muscle cell proliferation was significantly increased by conditioned media from human PBMC incubated with PTFE. Peripheral blood mononuclear cell adhesion to PTFE could not be antagonized by the beta 1 integrin ligand-containing peptide GRGDSP, but was attenuated by EDTA consistent with beta 2 integrin-mediated adhesion. Soluble scavenger receptor ligands at high concentrations had no effect on adhesion to PTFE excluding any contributory role of scavenger receptors in this interaction. Neutralizing antibodies to TNF-alpha significantly attenuated the mitogenic effect of PBMC/PTFE conditioned media and a marked increase in TNF-alpha secretion by PBMC on PTFE was detected by ELISA. These studies demonstrate that PBMC interaction with PTFE can promote proliferation of VSMC via increased production of TNF-alpha and perhaps other cytokines. Leukocyte interaction with PTFE causing enhanced secretion of TNF-alpha and consequent VSMC proliferation may account for the development of venous intimal hyperplasia in hemodialysis patients with arteriovenous grafts.