Early events of cellular infiltration during allograft rejection involve interactions between alloreactive lymphocytes and vascular endothelium. These interactions have been studied in an in vitro model of lymphocyte adherence to human arterial endothelial cell (HAEC) monolayers. Alloreactive lymphocytes primed against donor HLA antigens (DPL) or unrelated HLA antigens from a third party (TPL) were studied for their adherence to HAEC derived from organ transplant donors. DPL exhibited a degree of adherence to donor HAEC which was nearly twice that of the TPL population and developed a morphologically blastoid appearance. DPL adherence was dependent on the recognition of donor HLA antigens expressed on the HAEC surface and investigation of DPL and TPL adherence at various lymphocyte concentrations showed that the binding of DPL and TPL to HAEC was saturable. Monoclonal antibody (MoAb) directed against HLA class I antigens showed inhibition of only DPL adherence to HAEC monolayers expressing donor class I HLA antigens, whereas MoAb directed against other HAEC surface antigens failed to inhibit either the DPL or TPL populations. The results of this study suggest that in a transplant situation, lymphocyte activation and adherence to the graft endothelium is increased in the context of allorecognition.