Blood transfusions may have a beneficial or deleterious effect on graft survival. The purpose of the present study was to see whether cyclosporin A (CyA) could overcome the sensitizing effect of pretransplant blood transfusions and whether it would alter the beneficial effect of blood transfusions. Therefore, the effect of CyA was studied in transfused and nontransfused recipients by use of a rat cardiac allograft model. The BN/Ro and Wag/Ro strains were used. Each strain rejects a heart allograft from the other in 8 to 9 days when nontransfused recipients are involved. After conditioning with one donor-specific pretransplant blood transfusion, accelerated rejection is seen in the Wag/Ro to BN/Ro combination, whereas indefinite survival occurs in the reverse combination. CyA treatment results in indefinite graft survival in nonsensitized recipients of both strains but at a lower dosage in the BN/Ro to Wag/Ro combination. In transfused BN/Ro recipients, CyA prolongs heart allograft survival indefinitely, although higher doses are required (15 mg/kg) than in nonsensitized recipients; in the reverse combination, CyA does not interfere with the beneficial blood transfusion effect. The findings that CyA can prevent accelerated rejection in the Wag/Ro to BN/Ro combination and that it does not alter the beneficial effect in the reverse combination might mean that CyA is a useful drug even in sensitized recipients.