Accelerated coronary atherosclerosis (ACA) has been documented at autopsy and was noted at coronary angiography in seven patients, 11 to 48 months after cardiac transplantation. To delineate the importance of this problem, the risk factors and the therapeutic approaches in 7 patients who had ACA after heart transplantation were compared with those in 28 patients free of ACA at annual coronary angiography. Ischemic cardiomyopathy was the preoperative diagnosis in all but one patient in the ACA group. The age of the transplant recipients, total myocardial ischemic times and arterial blood pressures at follow-up were similar in both groups. Donor age averaged 31 +/- 3 years in the ACA group and 22 +/- 1 years in patients free of ACA. Preoperative cholesterol, triglyceride and high-density lipoprotein levels were lower in ACA-free patients and the low-density lipoprotein level was higher. At the last follow-up visit, serum lipid levels were similar in both groups. The incidence of acute rejection and of infection was slightly, but not significantly, higher in patients with ACA. The actuarial survival of ACA patients 4 years after transplantation was 30% +/- 20% compared with 100% for patients free of ACA (p less than 0.01). Actuarial rates of freedom from ACA and from death due to ACA were 73% +/- 11% and 81% +/- 11% respectively. Stepwise discriminant analysis showed that older donors and higher pretransplant triglyceride levels were independently related to the development of ACA after cardiac transplantation. In conclusion ACA remains an important cause of late death after heart transplantation. Although therapeutic measures are limited, prevention should focus on strict control of serum lipid levels after transplantation.