Acute vascular rejection of the coronary arteries in human heart transplants is characterized by a lymphocytic infiltrate and a thickened intima that contains numerous highly vacuolated cells. The origin of the vacuolated cells has been controversial. In this immunocytochemical and electron microscopic study of four patients with acute vascular rejection, the predominant cells in the coronary artery intima were host-derived lymphocytes and highly vacuolated smooth muscle cells. Lymphocytic infiltrates were composed of T cells with variable numbers of B cells. Macrophages were infrequent. Smooth muscle cells were identified by their reactivity to muscle-specific actin and ultrastructural features of a peripherally displaced elongated nucleus associated with abundant myofibrils. In addition, the vacuolated cells did not react with endothelial factor 8-related antigen or Ulex europaeus agglutinin, as would be expected of endothelial cells. The cytoplasmic vacuoles present in the smooth muscle cells appear to be swollen endoplasmic reticulum containing watery fluid consistent with the hypothesis that they result from altered ion movement across the plasma membrane in response to cellular injury.