Seven baboons underwent autotransplantation of the heart or heart and both lungs (group A). Eleven allografts were performed (group B) (nine orthotopic heart transplants and two en bloc transplants of the heart and both lungs). Radionuclide ventriculography was performed both pretransplant and at intervals posttransplant in all animals, and provided measurements of ejection fraction (EF) and left ventricular volumes (LVv) (end-diastolic volume [EDV], end-systolic volume [ESV], and stroke volume [SV]). In seven animals, a total of 20 endomyocardial biopsies were taken. Correlation was made between histopathological features of acute rejection seen on endomyocardial biopsy and changes in EF and LVv measured by radionuclide imaging. A significant increase of 12% in the EF (P<0.01) and significant falls in the LVv were observed in all animals (groups A and B) on the first posttransplant day, presumably a result of total cardiac denervation. EDV was reduced by 50% (P<0.005), ESV by 62% (P<0.0001), and SV by 43% (P<0.0001). In autografted baboons (group A) EF and LVv showed no further changes until reinnervation of the heart had occurred, when they reverted to pretransplant levels. In the allografted baboons (group B) further significant reductions in the LVv occurred as acute cardiac rejection progressed. From the first post-transplant day to the time of the final study before the animals' death, the EF decreased by 10% (P<0.01), the EDV by 38% (P<0.005), and SV by 73% (P<0.003): the decrease in ESV did not reach statistical significance. Measurement of EDV and SV by radionuclide ventricular function studies provides excellent correlation with changes of acute rejection seen on endomyocardial biopsy. These findings would suggest that radionuclide ventriculography may be a reliable diagnostic procedure to detect acute rejection in patients with heart transplants. © 1988 Grune & Stratton, Inc.