Coronary artery disease (CAD) is now the major limitation to long-term survival after cardiac transplantation. Its etiology remains unclear. The possible role of viral infection in the genesis of CAD stimulated the review of 102 patients transplanted since the introduction of triple drug immunosuppression (cyclosporine, azathioprine and prednisone) to assess the importance of posttransplant cytomegalovirus infection in the development of CAD in the cardiac graft. CAD occurred in 16 patients (16%). Recipient age and sex, donor age, pretransplant diagnosis, frequency of acute rejection episodes, HLA mismatch, cytomegalovirus infection, incidence of posttransplant systemic hypertension and diabetes mellitus, and mean triglyceride, cholesterol and cyclosporine levels were analyzed to assess their influence on the development of CAD. Only the occurrence of cytomegalovirus infection was found to be a significant factor (p = 0.007): infection occurred in 62% of patients with CAD and in only 25% of those without. These data support the existence of an association between cytomegalovirus infection and CAD after cardiac transplant. It is possible that the virus contributes to the initial injury to the coronary endothelium.