Allograft coronary artery disease (CAD) is the major determinant of long-term survival following heart transplantation (HTx). In a group of 210 heart transplant recipients, we diagnosed CAD in 54 (27.1%) by coronary angiography, postmortem examination or examination of the transplanted heart at the time of retransplantation. Retrospective analysis of potential risk factors for the development of CAD was performed for both immunological (rejection pattern, immunosuppressive therapy, cytomegalovirus [CMV] infection), and nonimmunological (hyperlipidemia, smoking, hypertension, diabetes mellitus, obesity) risk factors. The total number of rejection episodes correlated significantly with the occurrence of CAD (P less than 0.05), showing that patients who experienced two or more rejection episodes had an incidence of CAD of 40%, as opposed to a 23% incidence in patients who experienced no rejection. A composite rejection score derived from multivariate regression analysis of the severity, frequency, and timing of acute cardiac rejection episodes was found to correlate with the development of CAD (P less than 0.05). Postoperative arterial hypertension also correlated significantly with the onset of CAD (P less than 0.01), with a 92.6% incidence of hypertension in the group with CAD versus 76.3% in the group without CAD. Smoking after transplantation correlated significantly with the occurrence of CAD (P less than 0.05). There was no significant correlation with other analyzed factors in this group of patients. In this review, the development of CAD after heart transplantation correlated with treated allograft rejection. Aggressive treatment of hypertension and cessation of smoking may contribute to alleviation of this serious complication.