To investigate the mechanism of the beneficial effect of blood transfusions (BT) on subsequent kidney transplant survival, we have studied the influence of planned BT on lymphocyte reactivity in previously nontransfused uremic patients. A marked decrease in mixed-lymphocyte reactions (MLR) to the donor and to other unrelated cells was observed soon after the first BT in 38% of the patients. This effect waned thereafter, but additional transfusions led to more pronounced and prolonged reductions. A sustained and nonspecific reduction that appeared only after the second or third BT was observed in 24% of the patients. Other patients had only a transient decrease, but otherwise MLR were normal or even increased. Modifications of the response to mitogens or to soluble antigens were also noted but, except for PPD, they were not related to BT. Most of the lymphocyte suspensions in which proliferation was reduced after BT could inhibit the response of autologous cells taken before BT, when they were mixed together in three-cell experiments. Since these suspensions were usually not cytotoxic to the stimulating cells in direct 51Cr release assays, inhibition could be attributed to suppressor cells. These results indicate that nonspecific suppression to allogeneic cells can be generated in vivo by BT.