Successful pig-to-human xenotransplantation may expose swine endothelium to the human immune system. Since endothelial MHC class II expression is crucial in the genesis of an allogeneic lymphocyte response, the involvement of porcine MHC (SLA) class II molecules in the induction of human lymphocyte proliferation was studied. When cocultured with a confluent monolayer of irradiated porcine aortic endothelial cells (PAEC), human peripheral blood mononuclear cells (PBMC) incorporated tritiated thymidine. Monocyte depletion strongly reduced the magnitude of the lymphocyte proliferative response. Resting cultured PAEC were SLA class II-negative and an induction of these molecules during the xenogeneic mixed lymphocyte endothelial cell culture (XMLEC) was not observed. Moreover, the addition of an antibody directed against the SLA-DR molecule was without effect. Lymphocyte proliferation was also studied in response to SLA class II-positive stimulating cells--either human TNF-alpha-stimulated PAEC or porcine splenocytes. Induction of SLA class II molecules on PAEC had no effect on the human PBMC proliferative response. Moreover, human PBMC did not proliferate in response to porcine splenocytes. These results suggest (1) that SLA class II molecules are not involved in the induction of the human lymphocyte proliferative response and (2) that the endothelial nature of the stimulating cells plays a key role in this proliferation.