We have examined whether portal venous pretransplant transfusion, which has been shown to produce prolongation of rodent vascularized (small intestine, kidney) and nonvascularized (skin) allografts, in the absence of other nonspecific immunosuppression, can produce similar graft prolongation in animals receiving vascularized or nonvascularized xeno- (not allo-) grafts. Rat kidney or skin grafts were transplanted into mice after portal venous pretreatment with rat or mouse spleen cells. Animals in some groups received additional immunosuppressive regimens including drug therapy (methotrexate, cyclosporin A) or monoclonal antibody treatment (anti-CD4, anti-CD8). Animal survival and serum creatinine was followed daily, and lymphoproliferation, cytokine production (including cytokine mRNA in grafted mice) and anti-xenograft antibody production was measured at distinct time points postgrafting. Both portal venous pretransplant transfusion and anti-CD4 monoclonal antibody treatment led to increased graft survival. However, unlike the rodent allograft model, graft survival in these animals was not simply explained by altered Th1/Th2 ratios. Other mechanism(s), possibly including xenoantibody production, are likely of importance in the regulation of xenograft rejection.