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Since 1989, the immunosuppressive regimen used in all heart transplant (HTx) patients at our center has consisted of a combination of cyclosporin, azathioprine, and prednisone. No prophylactic cytolytic agents have been given. One hundred consecutive patients were followed for periods of 4–56 months (mean 27 months). The incidence of rejection was so low in the initial 18 patients that we felt confident about reducing the number of routine endomyocardial biopsies (EMBs) that were performed. The mean number of EMBs in this subgroup was 10 (median 11). In the next 20 patients, EMB was performed routinely on only three occasions during the 1st post-transplant year (at 2, 4, and 8 weeks). In the subsequent 62 patients, EMB was performed on post-transplant days 10, 20, 30, and 60. Further EMBs were performed after acute rejection episodes had been treated. No noninvasive methods of diagnosing rejection were employed. In 82 consecutive patients, therefore, the mean number of EMBs within the 1st year was five per patient (median four), with 58% undergoing fewer than five EMBs and 25% requiring more than five EMBs. In the entire group of 100 patients, the mean number of EMBs was 5.9. The incidence of acute rejection requiring increased therapy was 24%. Only 7% required i.v. steroids, two of whom (2%) also required ALG and/or OKT3, with 17% requiring increased oral immunosuppression alone. Actuarial survival was 98% at 30 days, 94% at 1 year, and 92% at 2 years. It is possible that we may have missed acute rejection episodes that resolved spontaneously. However, the excellent mediumterm results would suggest that any such rejection episode did not progress to become hemodynamically significant. It may be, therefore, that when an effective immunosuppressive regimen is utilized, the number of EMBs performed at many centers is excessive.