BACKGROUND--Failure of the donor (graft) heart is the main cause of mortality in the first month after orthotopic cardiac transplantation. In a preliminary study marked downregulation of cardiac beta adrenoceptor density was found in apparently normal donor hearts of recipients who developed severe cardiac failure soon after implantation. Cardiac beta adrenoceptors are an important factor in the development of cardiac failure in the human heart. The aim of this study therefore was to determine whether fatal graft failure in the first month after transplantation is associated with downregulation of beta adrenoceptor density in the donor heart. PATIENTS AND METHODS--Right ventricular endomyocardial biopsy specimens were taken from consecutive adult donor patients immediately before implantation. A previously described radioligand binding method was used to determine beta adrenoceptor density in consecutive patients who developed fatal graft failure and died within 1 month of transplantation and in a group of control donors transplanted during the same period. RESULTS--Perioperative fatal graft failure developed in 13 patients. Forty one specimens from donor hearts that were transplanted into recipients who did not develop fatal graft heart failure formed the control group. There were no systematic differences in donor or recipient characteristics between the graft heart failure and control groups. In particular donor catecholamine requirement and recipient pulmonary vascular resistance did not differ between groups. Total beta adrenoceptor density was reduced in the fatal graft heart failure group compared with that in the controls (13.4 (7) fmol/mg v 21 (7) fmol/mg; P < 0.01). There was a positive correlation between beta adrenoceptor density in the donor heart and time to death in the graft heart failure group (r2 = 0.3, P < 0.05). The beta adrenoceptor binding affinity (Kd) did not differ between the graft failure group and the controls (47 (6) pM v 44 (7) pM). CONCLUSION--The development of perioperative fatal cardiac failure after orthotopic cardiac transplantation is associated with downregulation of beta adrenoceptors in the donor heart before implantation.