We conducted a prospective longitudinal study to determine the clinical significance of endothelial adhesion molecule expression in endomyocardial biopsies from human cardiac allografts. Ten to 18 (mean 13) consecutive allograft biopsies were obtained from 20 serial human transplant recipients over a one-year period. A total of 267 biopsies was examined. The expression of endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, as well as the presence of CD3+ T cell infiltrates was assessed by immunocytochemical staining of frozen sections. Separate specimens taken at the same time were analyzed histologically for ischemic injury or rejection. ICAM-1--and, to a lesser extent VCAM-1--was expressed at low levels in normal biopsies. E-selectin was only expressed in 15% of histologically normal biopsy specimens. Ischemic injury noted in the immediate posttransplant period was associated with increased expression of all three adhesion molecules. VCAM-1 expression increased both with the degree of CD3+ T cell infiltrates (P < 0.001) and with the degree of rejection (P < 0.05). ICAM-1 increased over constitutive levels in association with diffuse CD3+ infiltrates (P < 0.001) and with rejection (P < 0.05). E-selectin was increased on occasional vessels in association with CD3+ infiltrates (P < 0.001), but was not associated with active rejection. Increases in E-selectin were most likely to occur in biopsies just prior to rejection episodes (odds ratio 3.3), and were least likely to occur in biopsies following rejection (odds ratio 0.3). ICAM-1, but not VCAM-1, was also elevated in prerejection specimens. VCAM-1 and ICAM-1 declined in postrejection specimens. These data suggest a dynamic pattern in the expression of endothelial cell adhesion molecules during the course of cardiac allograft rejection. This study also suggests that endothelial E-selectin expression may be a useful clinical marker of impending rejection. Finally, inducible VCAM-1 expression may be a helpful adjunct in the diagnosis of ongoing acute rejection, and decreases in its expression may be indicative of successful antirejection therapy.