Fifty-four patients (group I) underwent isolated heart transplantation between July 1983 and January 1987 and were immunosuppressed with oral prednisone and cyclosporine. Twenty-three patients (group II) were transplanted between January 1987 and June 1988 and were immunosuppressed with oral prednisone, azathioprine, and cyclosporine, with lower targeted cyclosporine blood levels. The groups were similar in sex distribution of both donors and recipients. Primary cardiomyopathy was the primary recipient diagnosis in two thirds of patients in both groups. Donor age, graft ischemic time, and length of recipient hospitalization after transplant were similar. There was a trend toward transplantation of older patients in group II, and group II patients were more likely to receive hearts from local donors. Actuarial survival at 24 months was 75% in group I and 92% in group II. Patients who had triple-drug immunosuppression had statistically less early rejection but more early infections that tended to be minor. Hypertension requiring treatment occurred in 63% of group I patients and 62% of group II patients within the first 9 months after transplantation. Elevation of serum creatinine greater than 2.0 mg/dl occurred in 34% of group I patients and 15% of group II patients. A triple-drug immunosuppressive protocol is associated with less early rejection but more early minor infectious episodes. Although the incidence of hypertension is not reduced, there is a trend toward less nephrotoxicity and better survival.