Right ventricular endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection of the heart allograft. Surveillance right ventricular endomyocardial biopsies are performed routinely at 3-month intervals in heart-lung transplant patients with uncomplicated conditions who have long-term follow-up. Recent observations of asynchronous heart and lung rejection, plus the impression that acute rejection was a rare phenomenon in long-term heart-lung transplant survivors, led us to analyze our experience with this technique to determine its clinical role. During the first 6 years of the heart-lung transplantation program at Stanford University Medical Center, only one episode of moderate acute rejection has occurred at greater than 4 months after heart-lung transplantation, despite greater than 160 surveillance right ventricular endomyocardial biopsies. This was in a patient who was recovering from a viral illness and had a subtherapeutic cyclosporine level of 38 ng/ml (as measured by radioimmunoassay). Fourteen patients (40%) have never had acute rejection, but freedom from acute rejection did not correlate with freedom from obliterative bronchiolitis or concentric coronary artery intimal hyperplasia. We conclude that in the long-term management phase (greater than 6 months after heart-lung transplantation), right ventricular endomyocardial biopsy should be performed for specific indications, rather than as a surveillance procedure.