Plasma levels of soluble CD8 (sCD8) and soluble CD4 (sCD4) in 44 patients with infectious mononucleosis (IM) were studied. A marked increase in sCD8 (22366 +/- 2702 U/ml; control: 219 +/- 10 U/ml; P < 0.0001) and significant increase in sCD4 (19.3 +/- 0.9; control: 8.1 +/- 0.2, P < 0.0001) strongly suggest activation of both CD8+ and CD4+ lymphocytes, which is important in restraining Epstein-Barr virus-infected B lymphocytes. Levels of sCD8 strongly correlated with the percentage and the absolute number of both CD8+ and CD8(+)-HLA-DR+ lymphocytes. In addition, we showed increased release of sCD8 from lymphocytes in vitro and increased ratio between plasma sCD8 and the number of CD8+ lymphocytes in blood, indicating that elevation of plasma sCD8 is due to expansion of CD8+ subset as well as increased sCD8 release from each CD8+ cell. Increased sCD4 release from CD4+ lymphocytes, the number of which is not increased in the blood during IM, was also seen. Patients with more severe fever had higher levels of sCD8 and sCD4. During convalescence sCD8 and sCD4 levels showed progressive decrease; however, even at 60-119 d after onset the levels of sCD8 and sCD4 remained higher than normal, suggesting prolonged lymphocyte activation. These results suggest that sCD8 and sCD4 are useful in monitoring immune activation during IM.