Limited clinical experience concerning heart transplantation across ABO blood group barriers suggests a high incidence of hyperacute rejection and poor patient outcome. Reported is a case of the short-term survival of an ABO-mismatched cardiac graft without evident adverse immunologic effects. A 41-year-old man with blood type O underwent heart transplantation receiving a blood type A2 donor organ. Cyclosporine-based immunosuppression was augmented with daily plasmapheresis and OKT3 therapy. Circulating anti-A antibodies were reduced quickly and held to a very low level with this regimen. The patient remained hemodynamically stable until retransplantation 4 days later. The explanted heart showed no evidence of cellular infiltrate or antibody deposition. Long-term success with the use of type A2 organs in type O recipients has been shown in select series with other types of solid organ transplants. Although this patient underwent retransplantation early, the lack of rejection phenomena gives evidence that the relatively low antigenicity of the A2 subtype may allow planned heart transplantation across this blood group barrier, either as a bridge or on a permanent basis.