Irradiated leukocytes or mononuclear leukocytes, from 16 out of 30 patients with Hodgkin's disease and from one patient with the Sézary syndrome, stimulated in culture subnormal (3H)thymidine incorporation by allogeneic lymphocytes from normal individuals. This abnormality was not demonstrated in any of 30 other patients with non-Hodgkin's lymphomas. Subnormal mixed leukocyte culture reaction activation was caused by suppression of the mixed leukocyte reaction by patients' cells. Inhibition of the reaction by patient mononuclear leukocytes was corrected when adherent cells were removed or when protein synthesis was inhibited with cycloheximide. The inhibitory cells were probably lymphocytes since selective removal of phagocytic cells did not remove the inhibition by other patient mononuclear leukocytes. The presence in culture of as few as 2,500 granulocytes per mm3 also reduced responses when target cells were from patients with Hodgkin's disease. Patient cells no longer suppressed the mixed leukocyte reaction after patients entered clinical remission which suggests that suppression is a reversible, disease-related abnormality. Thus, the immune deficiency with advance Hodgkin's disease caused by ly lymphocyte depletion may be compounded by a relative excess of suppressor lymphocytes. The overall immunodeficiency may be further compounded by suppression of immune response by granulocytes at even physiologic concentrations.