Background. Natural killer (NK) cells have been implicated in a process of delayed xenograft rejection occurring in pig-to-primate organ transplants. As tumor necrosis factor-α (TNF-α) induces expression of both adhesion receptors and major histocompatibility complex class I molecules on porcine endothelium, we investigated the effects of TNF-α on human NK cell adherence to and cytotoxicity of porcine aortic endothelial cell (PAEC) monolayers. Methods. Adherence of human NK cells was measured after PAEC treatment with increasing concentrations of TNF-α. Monoclonal antibodies (mAbs) against adhesion molecules on NK cells and PAEC were used in inhibition studies. Resting or TNF-α-treated PAEC were used as targets for NK lysis. Increasing titers of anti-swine leukocyte antigen (SLA) class I antibodies or pooled human immune globulin (IVIg) were used to reverse the effects of TNF-α on NK lysis. Results. NK cell adhesion to TNF-α-treated PAEC increased in a dose- dependent manner by a maximum of 44%, and was inhibited by mAbs against CD49d, CD11a, CD11b, CD18, and CD2, as well as porcine vascular cell adhesion molecules. In contrast, TNF-α treatment of PAEC reduced human NK lysis in a dose-dependent manner. Preincubation of TNF-α-treated PAEC with increasing concentrations of anti-SLA class I mAb increased NK lysis in a titer- dependent manner, and reversed the protective effect on human NK lysis by 77%. Treatment with Mg, containing antibodies against an α-helical region of HLA class I molecules, had a similar effect. Conclusions. These results imply that SLA class I molecules can bind to inhibitory receptors on human NK cells, and that these interactions can be augmented by increasing the level of SLA class I molecule expression on porcine endothelium. Strategies that can increase porcine endothelial cell expression of either swine or human major histocompatibility complex class I molecules may reduce human NK activity against porcine xenografts.