Heart-lung transplantation (HLT) unlike other solid-organ transplants involves transplantation of a large amount of lymphoid tissue; hence there is considerable potential for graft-versus-host reaction if there is an antigen mismatch between donor and recipient. Due to the shortage of suitable donors, minor ABO-mismatched HLT (group O organs given to A, B, or AB recipients) are performed. Of 84 consecutive HLT at Harefield Hospital, nine fully ABO-matched and nine ABO-mismatched HLT were studied. Six minor ABO-mismatched HLT patients had evidence of immune destruction of recipient's red cells. Haemolysis started from days 4-12 and lasted for a mean of 13 days; in four cases transfusion support was necessary. ABO antibodies incompatible with the recipient ABO antigens, but compatible with the donor, were found in the serum and red cell eluates of these patients. In two cases, these antibodies were detected for over one year after transplantation. These changes were not seen in the fully ABO-matched controls. Our findings suggest that donor-derived lymphocytes from group O organs continue to produce anti-A and/or anti-B after transplantation, and if the recipient is group A, B, or AB, mount a secondary immune response following antigenic stimulation by the recipient's differing ABO antigens. The specific transfusion management of these patients is discussed.