Infection remains the major cause of mortality and is a significant source of morbidity following heart transplantation. Between March 1978 and March 1986, 62 orthotopic heart transplants were performed at the University of Minnesota. There were 56 clinically significant infectious episodes in 31 of the 58 patients surviving the perioperative period. The era I (1978-1982) experience with antilymphocyte globulin, prednisone, and azathioprine and the era II (1982-1983) experience with high-dose cyclosporine and prednisone were associated with a high incidence of cytomegalovirus and fungal infections. The conversion to low-dose triple-drug immunosuppression with cyclosporine, prednisone, and azathioprine in 1983 (era III) has markedly reduced infectious deaths and altered the spectrum of clinical infection by decreasing serious fungal and cytomegalovirus infections. This protocol has also significantly reduced the incidence of rejection. The reduction of infection and rejection complications with triple-drug immunosuppression has led to improved patient survival of 94% at 1 year and 87% at 2 years.