This study aimed to investigate the pathological effects of chronic limb-threatening ischemia on the structural integrity of the great saphenous vein (GSV) wall. The analysis encompassed 89 cases in which the residual GSV segment, harvested prior to its use for infrainguinal peripheral artery bypass grafting, was submitted for pathological examination. Measurements were conducted on the intimal and medial thickness of the GSV, with a focus on the three key factors influencing foot severity—Wound (W), Ischemia (I), and foot Infection (fI). The clinical relevance of these variables was assessed using loss of primary graft patency as the endpoint. Multivariate analysis identified severe W cases (grades 2 and 3) as a significant factor contributing to loss of primary graft patency. In comparison to mild cases, severe W cases demonstrated a marked thickening of both the intima and media of the GSV, suggesting that advanced wound severity induces morphological alterations in the vein prior to placement. Further analysis of the GSV wall thickness before placement revealed no significant difference in intimal thickness between cases with and without endpoint occurrence; however, medial thickness was significantly increased in the endpoint occurrence group. The observed medial hypertrophy in the GSV of severe W cases may represent a critical factor linked to graft failure.