It has previously been demonstrated that blood transfusions (BT) can induce the generation of suppressor cells in the mixed lymphocyte reaction (MLR). We have further investigated whether regulation of the alloimmune response could also be observed at the cell-mediated lympholysis (CML) level. We have, therefore, prospectively analyzed the effect of the first 2 BT on cytotoxic T lymphocyte (CTL) differentiation in previously nontransfused uremic patients. Different patterns of CML changes were noted. In 7 cases, marked CML reduction was observed after the first BT, and in 7 others CML remained unchanged or even increased after the first BT, but reduced CML occurred after the second. Increased CML was noted in the last 4 cases. When present, reduction in CML after BT could indeed occur upon in vitro restimulation by cells of the specific donor, but also by those of other individuals regardless whether they shared HLA antigens. Post-BT lymphocytes the CML of which was decreased could inhibit CML of autologous pre-BT cells when used as an irradiated third-party at the initiation of the sensitization step. No correlation, however, was generally observed between MLR and CML suppressions when both were tested in parallel assays. CML reduction could occur in the presence of unchanged or increased MLR, and no cytotoxicity to the stimulating cells could be observed in direct cytolysis assays, so this inhibition can be attributed to suppressor cells of CTL differentiation that are generated in vivo after BT in man.