Hemodialysis vascular access dysfunction currently is a huge clinical problem. Although arteriovenous fistulas (AVFs) are the preferred form of permanent dialysis access, they continue to have significant problems with early AVF failure. Although inadequate dilatation of the venous segment was believed to have a role in early AVF failure, the exact pathogenesis of early AVF failure is unknown despite the magnitude of the clinical problem. Case series. Hemodialysis patients. Stenotic venous segments from 4 patients with early AVF failure were subjected to a detailed histological, morphometric, and immunohistochemical analysis. All 4 patients had significant luminal stenosis, primarily as a result of eccentric neointimal hyperplasia. This was confirmed through morphometric analysis, which documented intima-media area and thickness ratios that were greater than unity. Cellular phenotyping studies showed that the majority of cells within the region of neointimal hyperplasia were myofibroblasts, with smaller numbers of contractile smooth muscle cells. We described only a limited number of specimens. We show for the first time that aggressive neointimal hyperplasia is present in venous segment specimens from patients with early AVF failure. Future therapies to address this problem will need to target this pathogenetic pathway.