To clarify immune-mediated mechanisms in rheumatic heart disease caused by group A streptococcal infection, valve tissues from rheumatic patients with valvular heart disease who required valve replacement were studied for reactivity with monoclonal anti-CD4 or anti-CD8 monoclonal antibodies or anti-vascular cell adhesion molecule-1 (VCAM-1). At the valve surface, CD4(+) and CD8(+) T lymphocytes were adherent to valve endothelium and penetrated through the subendothelial layer. T cell extravasation into the valve through the surface valvular endothelium appeared to be an important event in the development of rheumatic heart disease. VCAM-1 was expressed on the valvular endothelium in rheumatic valves. Evidence suggested that the pathogenesis of rheumatic heart disease involved the activation of surface valvular endothelium with the expression of VCAM-1 and the extravasation of CD4(+) and CD8(+) lymphocytes through the activated endothelium into the valve. Lymphocytic infiltration through the valve surface endothelium has not been appreciated as a potential initiating step in disease pathogenesis.