Current immunosuppression protocols in heart transplantation commonly employ an inductive phase preoperatively, which often is followed by triple therapy (azathioprine, cyclosporine, and prednisone). From 1981 to June 1987, 119 heart transplants were performed in 114 patients. Group I (n = 19) received cyclosporine preoperatively and postoperatively, as well as steroid intraoperatively and postoperatively. Group II (n = 100) received antilymphocyte globulin postoperatively and interval cyclosporine orally 5 to 7 days postoperatively when the antilymphoblast globulin was discontinued. Methylprednisolone was given intraoperatively, and 1 mg/kg was given postoperatively. Steroid was tapered to 20 mg/day within 4 weeks. Cyclosporine was removed from the early postoperative regimen to reduce the deleterious renal effects. Steroid was used in low doses and tapered quickly to lessen steroid-related complications. There was one cyclosporine-related kidney failure in group I and none in group II. In no patient was cyclosporine discontinued because of adverse effects. The rate of rejection remains acceptable. There have been eight deaths as a result of rejection (three in group I and five in group II). Three patients have died of infection (one in group I and two in group II). Since January 1987 no postoperative protective isolation has been used. Overall survival is 77%, and no patient has exhibited late coronary atherosclerosis on follow-up coronary angiography. The regimen of immunosuppression that has evolved is safe and effective and has long-term benefits.