Most family members who are evaluated as kidney donors for children have high reactivity in a mixed lymphocyte culture test and are thus excluded from donation. Fifty children, most of whom had highly reactive mixed lymphocyte cultures with their donors, were challenged with three blood transfusions from their donors before transplantation and were tested for the development of lymphocytotoxic antibodies. Ten children (20%) became sensitized and had a positive T-cell or B-cell crossmatch. Sensitization occurred less frequently in children treated with azathioprine during donor-specific transfusions (11%) than in those not treated (26%), but the difference was not significant. Thirty-seven children received renal transplants from their blood donors after the donor-specific transfusions. There were no deaths, and only two patients had kidney failure. Actuarial kidney survival was 93% after 6 years. The use of donor-specific transfusion has increased the number of related-donor transplants performed and the results have been highly successful.