Numerous noninvasive techniques have been examined for the detection of acute rejection following cardiac transplantation, but none has proven sufficiently sensitive to replace the endomyocardial biopsy. A prospective study was performed in 92 heart transplant patients in order to test the hypothesis that mitral regurgitant ratio by two-dimensional echocardiography with Doppler flow mapping could detect moderate or severe acute allograft rejection. There were 82 rejection episodes identified, of which 40% were associated with mitral regurgitation by echo-Doppler at the beginning of the episode. With augmentation of immunosuppression during a rejection episode, there was a progressive fall in the degree of mitral incompetence (P = 0.03). The sensitivity of color Doppler studies in identifying rejection was low (60% of all rejection episodes had no associated mitral incompetence at the beginning of the episode), but the likelihood of rejection progressively increased with higher degrees of mitral regurgitation (P less than 0.01), approaching 60% when the echo-Doppler regurgitant ratio exceeded 15%. Echo-Doppler studies do not provide sufficient sensitivity to be useful as a screening technique for acute cardiac rejection, but high or increasing echocardiographic mitral regurgitant ratio is predictive of acute rejection and should indicate prompt endomyocardial biopsy.