The aim of this study was to search for signs suggestive of an ongoing immune-mediated reaction in failed human cryopreserved venous allografts. In 15 samples, the authors analyzed: (1) the pattern of morphological changes; (2) the density, distribution, and phenotype of leukocytic infiltrate; and (3) the expression of class II major histocompatibility complex (MHC) antigens and inducible adhesion molecules. Two groups of samples could be recognized. In samples explanted before 3 months after grafting, the structure of the vessel wall was preserved. A dense leukocytic infiltrate was present within the intima and around the numerous vasa vasorum located in medial and adventitial layers. Class II MHC antigens and cytokine-dependent molecules were induced on endothelial cells lining the vasa vasorum and on residual smooth muscle cells. In samples explanted after 3 months of evolution, the vessel wall has lost its normal structure and contained few vasa vasorum. A few leukocytes were detected around capillary vessels located in the peripheral connective tissue surrounding the graft. Class II MHC antigens and adhesion molecules were induced on endothelial cells lining the peripheral capillary vessels. These results suggest the involvement of an immune-mediated mechanism at the early stage of the evolution of failed human venous allografts.