BACKGROUND: Arteriovenous fistulas (AVFs) for hemodialysis frequently fail to mature because of inadequate dilation or early stenosis. The pathogenesis of AVF nonmaturation may be related to pre-existing vascular pathologic states: medial fibrosis or microcalcification may limit arterial dilation, and intimal hyperplasia may cause stenosis. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: Patients with chronic kidney disease (N = 50) undergoing AVF placement. PREDICTORS: Medial fibrosis, microcalcification, and intimal hyperplasia in arteries and veins obtained during AVF creation. OUTCOME & MEASUREMENTS: AVF nonmaturation. RESULTS: AVF nonmaturation occurred in 38% of patients despite attempted salvage procedures. Preoperative arterial diameter was associated with upper-arm AVF maturation (P = 0.007). Medial fibrosis was similar in patients with nonmaturing and mature AVFs (60% ± 14% vs 66% ± 13%; P = 0.2). AVF nonmaturation was not associated with patient age or diabetes, although both variables were associated significantly with severe medial fibrosis. Conversely, AVF nonmaturation was higher in women than men despite similar medial fibrosis in both sexes. Arterial microcalcification (assessed semiquantitatively) tended to be associated with AVF nonmaturation (1.3 ± 0.8 vs 0.9 ± 0.8; P = 0.08). None of the arteries or veins obtained at AVF creation had intimal hyperplasia. However, repeated venous samples obtained in 6 patients during surgical revision of an immature AVF showed venous neointimal hyperplasia. LIMITATIONS: Single-center study. CONCLUSION: Medial fibrosis and microcalcification are frequent in arteries used to create AVFs, but do not explain AVF nonmaturation. Unlike previous studies, intimal hyperplasia was not present at baseline, but developed de novo in nonmaturing AVFs.