ABSTRACT— It has been reported in human hepatic graft-versus-host disease (GVHD) that an attachment of lymphocytes to vascular wall, the feature called “endothelialitis”, is the most important predictive histologic sign of GVHD. However, its precise nature and significance in GVHD are still unknown. We developed experimental mouse GVHD across minor histocompatibility barriers and examined the lesion during a 14-month period after transplantation. The lesion was transiently found, appearing first at 4 days after transplantation, reaching a maximal level at 2 weeks and disappearing 5 weeks after transplantation. Electron microscopically, an intimate interaction between lymphocyte and endothelial cell was demonstrated. Lymphocytes showed irregular cytoplasmic processes and pseudopods and were in close contact with endothelial cells. Lymphocytes frequently penetrated in between and under the endothehal cells, and migrated into the perivascular spaces. Immunohistochemical analysis revealed that the vast majority of lymphocytes attached to the endothelial cells are helper/inducer T cells, indicating the cardinal role of helper/inducer T cell in lymphocyte-endothelial cell interactions. These results, together with previous evidence of the presence of Ia antigens and an antigen-presenting ability of vascular endothelial cells, suggest that the attachment of lymphocytes to the vascular endothelial cells in the early course of GVHD may represent an in situ morphologic representation of antigen presentation by endothelial cells to helper T cells.