Abstract: Fusobacterium nucleatum, a Gram-negative anaerobic organism, holds pathogenic roles in brain abscesses, pericarditis, as well as several oral diseases such as pulp infection, alveolar bone abscesses, and periodontal disease. F. nucleatum is one of the most commonly occurring species in the human gingival crevice and endodontal lesions. The interaction between bacterial species and the host defense mechanisms is considered to be crucial in determining the status of health and disease. Dr. B. J. Shenker (1987) has proposed a model of immunologic dysfunction occurring in the earliest stages of periodontal disease progression and is followed by a period of delayed or depressed active immune reactivity. This model is consistent with the fact that various periodontal pathogens are capable of producing immunosuppressive factors. F. nucleatum has immunosuppressive activities, but the exact mechanism of immunosuppression remains unclear. We have demonstrated that F. nucleatum induces apoptotic cell death in various eukaryotic cells. We used the following methods to study this phenomenon: Western analysis, cell culture, flow cytometry, ELISA, confocal microscopy, and DNA gel electrophoresis. We have shown that the induction of apoptotic cell death of immune cells by F. nucleatum strain PK1594 is dose-dependent, abrogated by heat and protease treatment, and correlated with abundant secretion of TNFα from the immune cells. We determined that F. nucleatum strains PK1594 and ATCC 23726 were able to induce cell death but not strain ATCC 49256. Upon co-culturing of F. nucleatum strain PK1594 with immune cells, aggregation of immune cells occurs. Upon inhibiting immune cell aggregation by protease and heat treatment of strain PK1594, and placing the co-culture in a matrigel, abrogation of immune cell death occurs. Formaldehyde fixed PK1594 retain their ability to aggregate and induce immune cell death. Hence, we have discovered that F. nucleatum strain PK1594 can induce cell death in immune cells. The strain's ability to cause aggregation of the immune cell is critical for inducing cell death. Understanding the mechanism of pathogenesis of F. nucleatum will allow us to design better preventive and treatment modalities.