Background. Because allograft rejection results from specific T-cell activation by donor human leukocyte antigens (HLA), new immunomodulatory therapies for organ-transplant recipients are used to selectively block T-cell activity without global immunosuppression. We investigated whether blockade of the high-affinity interleukin (IL)-2 receptor effectively prevented T-cell alloreactivity in cardiac transplantation. Methods and Results. A study of a humanized monoclonal antibody against the high-affinity IL-2 receptor (daclizumab) was performed in 70 adult, cardiactransplant recipients. Patients were stratified based on the degree of donor-recipient HLA-DR matches. Primary and secondary endpoints were incidence and frequency of high-grade allograft rejections, IL-2-dependent, T-cell outgrowth from biopsy sites as measured by lymphocyte growth assay, and production of anti-HLA antibodies. Treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months posttransplantation; in this group 0 of 13 (0%) treated with daclizumab experienced at least one high-grade rejection versus 3 of 13 (23%) controls (P=0.05). In addition, 1 of 12 (9%) daclizumab-treated patients experienced one or more episodes of IL-2-dependent, T-cell outgrowth versus 5 of 12 (42%) patients in the untreated group (P=0.05). In contrast, daclizumab used at the same dose and schedule was not as effective in fully HLA-DR-mismatched recipients. After cessation of daclizumab, allograft rejection increased to levels seen in controls. Conclusions. IL-2-receptor blockade is effective for preventing alloreactivity and high-grade rejection in cardiac transplantation; however, its efficacy seemed to be influenced by the degree of donor-recipient, HLA-DR locus mismatching.