To examine the functional changes that accompany the development of rejection of the orthotopically transplanted heart, radionuclide ventriculograms, right heart catheterizations, and endomyocardial biopsies were performed at weekly intervals during the posttransplantation hospitalization of 53 consecutive transplant recipients. Left ventricular ejection fraction decreased in those (n = 10) who had sequential biopsies that changed from no rejection to moderate rejection (63% ± 7% to 57% ± 7% respectively, p = 0.007). There was an associated decrease in the peak ejection rate (4.4 ± 1.0 to 3.9 ± 0.8 end-diastolic volumes per second, p = 0.008) and an increase in the time to peak ejection rate (137 ± 27 msec to 153 ± 20 msec, p = 0.004) that accompanied the development of rejection. There was a similar decrease in left ventricular ejection fraction in those (n = 9) who had sequential biopsies that changed from no rejection to mild rejection (63% ± 6% to 59% ± 8%, p = 0.009). Only two of 19 patients whose biopsies changed from no rejection to either mild or moderate rejection did not have an associated decrease in ejection fraction. In patients who had a blopsy that showed definite rejection, which was then followed by histologic resolution after treatment (n = 11), left ventricular ejection fraction increased from 56% ± 8% to 61% ± 8%, p = 0.03. There were no significant changes in any of the parameteres of diastolic function or in any of the hemodynamic parameters measured, which were associated with either the development or resolution of rejection. These data indicate that measurable changes in left ventricular ejection fraction occur in association with the development of histologic rejection of the transplanted heart and can be detected by radionuclide ventriculography.