With the demand for organ transplants increasing, xenograft transplantation is being considered. A major obstacle to a solution to fulfilling this demand is xenograft rejection. Histologic evidence indicates that the vascular endothelial cell (VEC) is involved in both humoral and cellular aspects of xenograft rejection. To study this phenomenon murine VEC and splenocytes were used in a mixed lymphocyte/endothelial cell culture and in a mixed lymphocyte culture with human peripheral blood mononuclear cells as responders. The VEC is a much better stimulator than the splenocyte. Removal of macrophages and B cells from the human peripheral blood mononuclear cells has no effect on the response to the VEC. The VEC acts as a target for humoral responses in the complement-dependent cytotoxicity and the antibody-dependent cell-mediated cytotoxicity. The VEC is killed in these two assays, which indicates the importance of the VEC in humoral rejection. These data indicate that the VEC is an important cell in xenogeneic immune reaction and may be pivotal in xenograft rejection.