Purpose: To determine why some vein grafts fail, we prospectively studied the relationship between the histologic condition of the greater saphenous vein (GSV) at the time of grafting and subsequent stenosis of the vein graft. Methods: Ninety-four remnant segments of GSVs were obtained at the time of infrainguinal bypass in 91 patients and were perfusion fixed before histologic and ultrastructural examination. All bypass grafts were evaluated clinically and by duplex ultrasonography at regular intervals from 1 to 30 months after operation. All 24 grafts that developed lesions that caused thrombosis (failed grafts) or flow reduction (failing grafts) underwent arteriography and appropriate operative or other interventional correction of the causative lesion. Results: There was no significant difference in the incidence of coronary artery disease, kidney disease, hypertension, or history of smoking in patients with normally functioning and failed or failing grafts. Diabetes occurred with an increased frequency in failed or failing grafts (p = 0.056). At the time of their insertion, GSVs that subsequently developed significant lesions had thicker walls (0.72 ± 0.33 mm) compared with normally functioning grafts (0.58 ± 21 mm; p < 0.02). Most of this difference was related to a significantly thicker intima (0.27 ± 0.17 vs 0.11 ± 0.7 mm; p < 0.0001). Another significant finding was the presence of subendothelial spindle-shaped cells greater than five cell layers thick. This occurred more often in pregraft biopsies from grafts that developed significant lesions (70.4% vs 7.5%, p < 0.0001). Electron microscopic examination of these cells demonstrated a subpopulation of poorly differentiated cells with few fibers and many vesicles. Four of 24 (17%) failed or failing grafts had evidence of vein wall calcification at the time of vein grafting. This was seen in only one (1.4%) of 70 normally functioning grafts without lesions (p < 0.005). Conclusions: We conclude that GSVs with thick and calcified walls or hypercellular intima at the time of grafting are at increased risk of developing intragraft lesions that may lead to graft failure. Frequent duplex ultrasonography surveillance is particularly warranted for such high-risk grafts.