Blood transfusions can affect the immune response in two opposite ways. They may either lead to immunization or to tolerance induction. Immunization is reflected by the induction of HLA alloantibodies and T cell activation while the induction of tolerance is suggested by the enhanced graft survival in transfused versus non-transfused recipients. The immunological mechanism leading to downregulation of the alloimmune response is not clear. One possible explanation is the induction of a Th2 response by non-professional antigen presentation by the transfused blood cells. On the other hand, evidence is accumulating that the degree of HLA compatibility between transfusion donor and patient is a determining factor. Transfusions sharing at least one HLA-DR antigen with the recipient induce tolerance while fully HLA-DR mismatched transfusions lead to immunization. The importance of the degree of HLA-DR sharing suggests a central role for CD4+ regulatory T cells. We hypothesize that indirect recognition of an allopeptide in the context of self-HLA-DR on the transfusion donor by CD4+ T cells of the recipient might be the clue to tolerance induction. Preliminary data show indeed that CD4+ T cells specific for an allopeptide in the context of self HLA-DR are able to downregulate the alloimmune response of autologous T cells. Further analysis of transplanted patients, who have received an HLA-DR shared transfusion, should reveal whether such CD4+ regulatory T cells are indeed responsible for the beneficial effect of pretransplant blood transfusions.