Blood transfusions can induce broadly reactive anti-HLA cytotoxic antibodies, particularly in patients who have had previous transplants or pregnancies. To evaluate if HLA-matched transfusions were less immunogenic, renal transplant candidates at high risk of becoming sensitized were transfused with blood from partially or totally HLA-matched donors. The study was performed in multiparous patients who in addition had low level antilymphocyte antibodies detected by flow cytometry. Only 1/24 patients (4.2%) developed cytotoxic antibodies. Crossover studies were possible in 3 patients. In 2 patients the HLA-matched transfusions did not elicit a response, but the patients produced cytotoxic antibodies of broad reactivity when they were subsequently transfused with random donor blood. The third patient developed cytotoxic antibodies after transfusions mismatched for only one HLA-A,B antigen. Subsequent transfusions mismatched for a different antigen did not, in contrast, result in sensitization. These results demonstrate that HLA-matched transfusions, unlike regular and leukocyte-free transfusions evaluated in previous studies, can prevent sensitization in patients with a high probability of becoming untransplantable if transfused with random donor blood.