We have examined soluble sonic extracts prepared from several strains of Centipeda periodontii for their ability to alter human lymphocyte function. These organisms were isolated from subgingival plaque of patients with periodontal disease. We found that sonicates from several, but not all, strains of C. periodontii caused a dose-dependent inhibition of lymphocyte responsiveness to concanavalin A, phytohemagglutinin, pokeweed mitogen, and formalinized Staphylococcus aureus. Inhibition was associated with a concomitant decrease in cell viability assessed by trypan blue exclusion, 51Cr release, and electron microscopy. The maximal number of dead cells was observed 20 to 24 h after exposure to the sonic extract. Susceptible cells include human lymphocytes (both B and T), monocytes, and erythrocytes, whereas polymorphonuclear cells, murine L-929 fibroblasts, and sheep erythrocytes were not affected. Preliminary characterization of the cytotoxic activity indicates that it is heat labile and trypsin sensitive and has an M(r) of 60,000. It has been proposed that impaired host defense may play a pivotal role in the pathogenesis of periodontal diseases. The data presented in this paper suggest that immunosuppression (local or systemic or both) could be initiated by C. periondontii. This immunosuppression may alter the nature and consequences of host-parasite interactions, thereby enhancing the pathogenicity of C. periodontii itself or some other opportunistic organism.