To determine the role of maintenance steroids in a cyclosporine and azathioprine immunosuppressive regimen, 112 heart transplant recipients were prospectively randomized to group I (n = 59; cyclosporine, azathioprine, and prednisolone) or group II (n = 53; cyclosporine and azathioprine). All patients received 7 days of induction with antithymocyte globulin. Patients receiving double-drug therapy who required four treatments for rejection were converted to maintenance steroids. This was necessary in 47% of the patients. Actuarial survival at 5 years was 82% in group I and 85% in group II. Linearized rejection in the first 3 months was lower with triple-drug therapy than with double-drug therapy (1.5 +/- 0.18 versus 2.3 +/- 0.23 episodes/100 patient days, p less than 0.01) but did not differ beyond 3 months. No significant differences were noted in 3-year left ventricular ejection fraction (0.56 +/- 0.09 versus 0.58 +/- 0.12 units), serum creatinine level (0.14 +/- 0.04 versus 0.14 +/- 0.03 mmol/L), or number with coronary artery disease (10 versus 13), diabetes, or bone complications. Patients receiving triple-drug therapy, however, had higher serum cholesterol level at 3 years (6.2 +/- 0.9 versus 5.4 +/- 1.2 mmol/L; p = 0.022) and required more antihypertensive agents (1.3 +/- 0.8 versus 0.8 +/- 0.6; p = 0.016). Similar trends emerged when patients receiving true double-drug therapy were compared with those patients who were "converted." Therapy with double versus triple immunosuppressive therapy results in similar 5-year survival and systolic function, using this protocol of converting recurrent rejectors on double-drug therapy to maintenance steroids.(ABSTRACT TRUNCATED AT 250 WORDS)