We report our initial experience with three patients who received heart-lung transplants. The primary immunosuppressive agent used was cyclosporin A, although conventional drugs were also administered. In the first patient, a 45-year-old woman with primary pulmonary hypertension, acute rejection of the transplant was diagnosed 10 and 25 days after surgery but was treated successfully; this patient still had normal exercise tolerance 10 months late. The second patient, a 30-year-old man, underwent transplantation for Eisenmenger's syndrome due to atrial and ventricular septal defects. His graft was not rejected, and his condition was markedly improved eight months after surgery. The third patient, a 29-year-old woman with transposition of the great vessels and associated defects, died four days postoperatively of renal, hepatic, and pulmonary complications. We attribute our success to experience with heart-lung transplantation in primates, to the use of cyclosporin A, and to the anatomic and physiologic advantages of combined heart-lung replacement. We hope that such transplants may ultimately provide an improved outlook for selected terminally ill patients with pulmonary vascular disease and certain other intractable cardiopulmonary disorders.