Vascular endothelial cells (VEC) are clearly immunogenic and express antigens unique to vascular endothelial cells. The observation that peripheral blood monocytes also express this VEC antigen system made prospective testing feasible. Preformed antibody to the VEC/monocyte antigen system of the donor usually leads to graft rejection in HLA-identical combinations, but antibody directed against donor monocytes exclusively (monocyte-specific antigens) appears to be benign. Clearly the VEC antigen system is an important immunogen in HLA-identical living-related donor combinations--and, in addition, this antigen system may be equally important in the non-HLA-identical combinations. The identification of antibody directed against the VEC/monocyte antigens of the donor is frequently masked by the concurrent development of anti-HLA antibody. Preliminary family segregation studies support the concept of genetic linkage between the VEC/monocyte antigen system and the major histocompatibility complex. A group of 153 consecutive, prospective monocyte crossmatches performed have yielded approximately a 7% incidence of positive monocyte crossmatches, with traditional crossmatches being negative. This frequency of patients sensitized to the VEC/monocyte antigens of the donor could conceivably account for up to 70% of the observed early graft loss in living-related donors. We think a positive monocyte crossmatch to the donor in the presence of positive reactivity to concordant VEC and monocytes remains a contraindication to transplantation.