The posttransplant production of antibodies against cryopreserved donor cells was studied in 50 consecutive cadaveric kidney graft recipients and in 23 additional patients selected for acute rejection. Serum was obtained twice weekly during the first 3 weeks posttransplant and then monthly for 6 months. IgM and IgG anti-T cell Abs were measured by 2-color flow cytometry. Results were analyzed in conjunction with the patients' demographics, previous sensitization, HLA-matching, posttransplant blood transfusions, incidence of delayed function, rejection episodes, and biopsy results. Antidonor antibodies, predominantly IgG, were detected in 19/48 (40%) of the patients proximate to the time of rejection. In contrast, antibodies were seen in only 2/22 (9%) of nonrejecting patients, and these antibodies were exclusively IgM. Younger patients were more likely to have antibody-mediated rejections. Cytotoxic antibody reactivity against panel cells developed or increased posttransplant in some patients, but it did not correlate with rejection. Previous sensitization and posttransplant transfusions favored the development of posttransplant panel reactivity but not of antidonor antibodies. Most rejections, including those associated with antidonor antibodies, were reversed by antirejection therapy. We conclude that antidonor antibodies are involved in a significant proportion of rejection episodes and that the damage induced does not necessarily culminate with loss of the graft.