The number of cardiac transplant procedures performed each year continues to increase and may exceed 1,600 procedures in 1987. In these patients, the diagnosis of rejection is obtained from serial endomyocardial biopsy. The absence of clinical symptoms associated with allograft rejection with cyclosporine therapy has necessitated a predetermined routine biopsy frequency that averages 10-15 biopsies per patient in the first posttransplant year. Traditionally, fluoroscopy has been used to guide the biopsy, but this technique has a number of negative features, including cumulative radiation exposure in the physician and the patient, limited portability, and the limited area of access (intraventricular septum) for biopsy. In contrast, echocardiography provides greater portability and flexibility for location of procedure performance, eliminates radiation exposure, provides important information about cardiac function, and safely allows biopsy of any area of the right ventricle, including the free wall and apex. We performed over 4,700 individual biopsies for evaluation of rejection in 58 patients who underwent orthotopic cardiac transplantation. Fluoroscopy was not required for any of the echocardiography-guided biopsies, and only two complications occurred in 4,700 biopsies. We propose, therefore, that echocardiography is a useful alternative or adjunct to fluoroscopy for guiding endocardial biopsy and is a technique that can be learned easily by anyone now performing biopsies.