We hypothesized that the venous limb of an arteriovenous (AV) fistula would evince up-regulation of genes relevant to vascular remodeling along with neointimal hyperplasia and relevant histological changes. Using the aorto-caval model of an AV fistula model in the rat, we demonstrate marked up-regulation in such proinflammatory genes as monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and endothelin-1, 2 weeks after the creation of the fistula. Neointimal hyperplasia occurred in variable degrees by 5 weeks after establishing the fistula, and by 16 weeks, such neointimal hyperplasia was progressive and pronounced; at this time point, abundant extracellular matrix was also observed. Smooth muscle cells were present in the hyperplastic neointima as evidenced by staining for alpha-smooth muscle actin; ultrastructurally, smooth muscle cells with a synthetic as well as a contractile phenotype were readily observed. Accumulation of extracellular matrix in the model at 16 weeks was accompanied by increased expression of transforming growth factor-beta1 mRNA, the latter finding contrasting with the suppression of transforming growth factor-beta1 mRNA observed in this model at 2 weeks. In summary, we describe marked up-regulation in proinflammatory genes and progressive neointimal formation in the venous vasculature in an AV fistula model in the rat. We suggest that such alteration in gene expression and histological injury, in conjunction with the relative simplicity of this model, offer a new approach in the study of such timely biological and clinically relevant phenomena as differential gene expression in response to hemodynamic forces, processes involved in vascular remodeling, mechanisms of injury in venous bypass grafts, and mechanisms of dysfunction of AV fistulae used in hemodialysis.