Probucol, a well-tolerated new drug with moderate hypocholesterolemic effect in the general population, was evaluated in hypercholesterolemic (greater than 300 mg/dl) cardiac transplant recipients. Nine patients received probucol, 500 mg twice daily, in a single-blind, placebo-controlled trial lasting 20 weeks. Six patients responded with cholesterol falls of -20% (mean, -13.2%), and 1 patient showed minimal change. One patient developed cardiac rejection and was excluded, and another responded paradoxically and was returned to previous therapy. In 1 patient, probucol was readministered, and a similar favorable response occurred, which has been sustained for over 6 months. For the group completing the study, low-density lipoprotein (LDL) cholesterol fell by 15.4%, accounting for the major portion of overall change in plasma cholesterol. High-density lipoprotein (HDL) cholesterol also fell (-15.6%), and the LDL/HDL ratio was unchanged. Triglycerides and very low density lipoprotein cholesterol showed variable responses with no overall change. Probucol was universally well tolerated, without adverse clinical or laboratory effects. In conclusion, probucol may effect a moderate hypocholesterolemic response in hyperlipidemic recipients of cardiac transplantation, despite long-term maintenance therapy with corticosteroids. However, efficacy should be individually documented. The long-term effect of probucol on the natural history of coronary artery disease in these patients remains to be determined, particularly in view of its effects on HDL cholesterol.