Serial serum samples from 266 recipients of primary renal allografts were monitored posttransplant for the presence of panel reactive lymphocytotoxic antibodies (PRA). The minimum posttransplant follow-up period was 18 months. Patients were classified according to whether or not they produced PRA before and/or after transplantation. The groups were as follows: PRA negative before and after transplant, -/-, 171; PRA positive before and negative after transplant, +/-, 5; PRA positive before and positive after transplant, +/+, 27; PRA negative before and positive after transplant, -/+, 63. Actuarial graft survival at 1 year for each group was 81.3%, 100%, 70.4%, 47.6%, respectively. Fifty-five of the 63 -/+ recipients were retrospectively crossmatched with posttransplant sera against stored donor lymphocytes. Of these, 50 (91%) were posttransplant cross match positive, and 37 (67%) have lost their grafts. In 23 of the 26 cases where an anti-HLA specificity was defined, the antibody was directed against antigens present in the donor but not in the recipient. These results clearly indicate that the production of PRA in recipients of renal transplants is associated with antidonor reactivity and poor graft outcome. The fact that these PRA were often directed against donor HLA antigens emphasizes one of the hazards of mismatching for HLA at transplantation.