We have recently observed that the HLA-DR match between recipients and transfusion donors influences the beneficial effect of blood transfusions on allograft survival. To examine the immunologic effects of one-HLA-DR-Ag-matched and completely DR-mismatched transfusions, transfusion-induced changes in cell-mediated lympholysis (CML) were investigated. Blood donor directed CTL activity was measured in vitro before and after blood transfusion in 56 candidates for organ transplantation who received planned HLA-typed blood. We report that blood donor-directed CTL activity increased substantially after a single transfusion mismatched with the recipient for two HLA-DR Ag (p less than 0.0001). A transfusion matched for one HLA-DR Ag did not enhance CTL activity. No correlation was found between CTL reactivity and sharing of HLA class I Ag. The present study supports our previous observation that matching for at least one HLA class II Ag (HLA-DR) between transfusion recipient and blood donor is required if immunization by blood transfusion is to be avoided. These data show that the presence or absence of "autologous" HLA-DR Ag on the leucocytes of the transfusion donor plays a decisive rol whether immunization or immune suppression will ensue.