BACKGROUND In rodents it has been demonstrated that blockade of the CD40-CD154 (CD40L) pathway at the time of donor-specific blood transfusion (DST) can result in indefinite graft survival. Because it has been reported in the past that DST in monkeys can have a favorable effect on graft outcome and that blockade of the CD40-CD154 pathway can lead to prolonged kidney graft survival in monkeys, we have combined anti-CD154 treatment with DST in a monkey kidney graft model. The aim of this study was to investigate the immunosuppressive potential of blocking the CD40-CD154 interaction at the time of a DST in rhesus monkeys. METHODS One donor-derived blood transfusion was given on day -15 after the first anti-CD154 injection. The anti-CD154 antibody was given on days -15, -13, -11, -9, and -7. The kidney was transplanted on day 0. Cyclosporine was given after kidney trans-plantation. RESULTS No major difference in graft survival was observed between the groups. The animals died due to grade II acute rejection. At the time of transplantation, no antibody response could be detected directed against donor antigens. After transplantation, all animals surviving for more than 3 weeks had antidonor antibodies. There were no differences in the intragraft events analyzed by real time reverse transcriptase-polymerase chain reaction. CONCLUSIONS DST under the cover of relatively high levels of anti-CD154 failed to result in prolonged graft survival or prevent the formation of antidonor antibodies, when cyclosporine was given after transplantation.